mercaptopurine and Neoplasms

Pharmacogenomic insights provide an opportunity to optimize medication dosing regimens and patient outcomes. However, the potential for interindividual genomic variability to guide medication dosing and toxicity monitoring is not yet standard of care. In this review, we present advances for the thiopurines, anthracyclines and vincristine and provide perspectives on the actionability of pharmacogenomic guidance in the future.. The current guideline on thiopurines recommends that those with normal predicted thiopurine methyltransferase and NUDT15 expression receive standard-of-care dosing, while 'poor metabolizer' haplotypes receive a decreased 6-mercaptopurine starting dose to avoid bone marrow toxicity. Emerging evidence established significant polygenic contributions that predispose to anthracycline-induced cardiotoxicity and suggest this knowledge be used to identify those at higher risk of complications. In the case of vincristine, children who express CYP3A5 have a significantly reduced risk of peripheral neuropathy compared with those expressing an inactive form or the CYP3A4 isoform.. The need for adequately powered pediatric clinical trials, coupled with the study of epigenetic mechanisms and their influence on phenotypic variation and the integration of precision survivorship into precision approaches are featured as important areas for focused investments in the future.

Topics: Cardiotoxicity; Child; Humans; Medical Oncology; Mercaptopurine; Neoplasms; Pharmacogenetics

Thiopurines, available as azathioprine, mercaptopurine, and thioguanine, are immunomodulating agents primarily used to maintain corticosteroid-free remission in patients with inflammatory bowel disease. To provide a state-of-the-art overview of thiopurine treatment in inflammatory bowel disease, this clinical review critically summarises the available literature, as assessed by several experts in the field of thiopurine treatment and research in inflammatory bowel disease.

Topics: Azathioprine; Drug Therapy, Combination; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Infliximab; Mercaptopurine; Neoplasms; Risk Factors; Thioguanine

6-Mercaptopurine (6-MP) and 6-thioguanine (6-TG), two anticancer drugs, have high systemic toxicity due to a lack of target specificity. Therefore, increasing target selectivity should improve drug safety. Areas covered: The authors examined the hypothesis that new prodrug designs based upon mechanisms of kidney-selective toxicity of trichloroethylene would reduce systemic toxicity and improve selectivity to kidney and tumor cells. Two approaches specifically were investigated. The first approach was based upon bioactivation of trichloroethylene-cysteine S-conjugate by renal cysteine S-conjugate β-lyases. The prodrugs obtained were kidney-selective but exhibited low turnover rates. The second approach was based on the toxic mechanism of trichloroethylene-cysteine S-conjugate sulfoxide, a Michael acceptor that undergoes rapid addition-elimination reactions with biological thiols. Expert opinion: Glutathione-dependent Michael addition-elimination reactions appear to be an excellent strategy to design highly efficient anticancer drugs. Targeting glutathione could be a promising approach for the development of anticancer prodrugs because cancer cells usually upregulate glutathione biosynthesis and/or glutathione S-transferases expression.

Topics: Animals; Antineoplastic Agents; Drug Design; Glutathione; Glutathione Transferase; Humans; Kidney; Mercaptopurine; Molecular Targeted Therapy; Neoplasms; Prodrugs; Thioguanine

The oxidative pentose phosphate pathway (PPP) contributes to tumour growth, but the precise contribution of 6-phosphogluconate dehydrogenase (6PGD), the third enzyme in this pathway, to tumorigenesis remains unclear. We found that suppression of 6PGD decreased lipogenesis and RNA biosynthesis and elevated ROS levels in cancer cells, attenuating cell proliferation and tumour growth. 6PGD-mediated production of ribulose-5-phosphate (Ru-5-P) inhibits AMPK activation by disrupting the active LKB1 complex, thereby activating acetyl-CoA carboxylase 1 and lipogenesis. Ru-5-P and NADPH are thought to be precursors in RNA biosynthesis and lipogenesis, respectively; thus, our findings provide an additional link between the oxidative PPP and lipogenesis through Ru-5-P-dependent inhibition of LKB1-AMPK signalling. Moreover, we identified and developed 6PGD inhibitors, physcion and its derivative S3, that effectively inhibited 6PGD, cancer cell proliferation and tumour growth in nude mice xenografts without obvious toxicity, suggesting that 6PGD could be an anticancer target.

Topics: AMP-Activated Protein Kinase Kinases; AMP-Activated Protein Kinases; Humans; Lipogenesis; Neoplasms; Oxidative Stress; Pentose Phosphate Pathway; Phosphogluconate Dehydrogenase; Protein Serine-Threonine Kinases; Ribulosephosphates; Signal Transduction

The use of thiopurines is well established in the management of inflammatory bowel disease. A wealth of data and experience, amassed over several decades, supporting their efficacy has recently been challenged by trials that failed to show a benefit in Crohn's disease when used early in the disease course, although other trials continue to support their role both as monotherapy and in combination with anti-TNF. Recent reports of previously unrecognized toxicity have also emerged. Fortunately, the absolute incidence of serious toxicity remains low, and an improved understanding of how best to minimize risk and the recognition of groups of patients at higher risk of toxicity from thiopurines means that they remain a relatively safe therapy in the majority of patients. In this paper, we review the literature evaluating the role of thiopurines in inflammatory bowel disease as well as their toxicity. We conclude that education regarding the spectrum of thiopurine side effects and optimal monitoring during therapy may help with optimizing safety and efficacy of these important medications.

Topics: Azathioprine; Chemical and Drug Induced Liver Injury; Colitis, Ulcerative; Crohn Disease; Humans; Immunosuppressive Agents; Mercaptopurine; Nausea; Neoplasms; Neutropenia; Opportunistic Infections; Pancreatitis

Historically genetics has not been considered when prescribing drugs for children. However, it is clear that genetics are not only an important determinant of disease in children but also of drug response for many important drugs that are core agents used in the therapy of common problems in children. Advances in therapy and in the ethical construct of children's research have made pharmacogenomic assessment for children much easier to pursue. It is likely that pharmacogenomics will become part of the therapeutic decision making process for children, notably in areas such as childhood cancer where the benefits and risks of therapy are considerable.

Topics: Child; Codeine; Drug Discovery; Drug-Related Side Effects and Adverse Reactions; Humans; Mercaptopurine; Neoplasms; Pediatrics; Pharmacogenetics; Precision Medicine

In the past decade, advances in pharmacogenetics and pharmacogenomics (PGx) have gradually unveiled the genetic basis of interindividual differences in drug responses. A large portion of these advances have been made in the field of anticancer therapy. Currently, the US FDA has updated the package inserts of approximately 30 anticancer agents to include PGx information. Given the complexity of this genetic information (e.g., tumor mutation and gene overexpression, chromosomal translocation and germline variations), as well as the variable level of scientific evidence, the FDA recommendation and potential action needed varies among drugs. In this review, we have highlighted some of these PGx discoveries for their scientific values and utility in improving therapeutic efficacy and reducing side effects. Furthermore, examples are also provided for the role of PGx in new anticancer drug development by revealing novel druggable targets.

Topics: Antineoplastic Agents; Capecitabine; Deoxycytidine; Drug Discovery; Fluorouracil; Genetic Variation; Humans; Mercaptopurine; Methyltransferases; Neoplasms; Pharmacogenetics; Polymorphism, Single Nucleotide; Precision Medicine

Thiopurine agents have been shown to be effective in maintaining remission in patients with Crohn's disease. There is less evidence for the efficacy of these treatments in ulcerative colitis. Consequently, the effect of thiopurines in the latter disease continues to be the subject of debate and controversy remains on whether these drugs are equally effective in both diseases. The present article aims to review, from a practical point of view, the evidence of the efficacy of thiopurines in ulcerative colitis, current indications for this treatment, safety in patients with inflammatory bowel disease and the treatment optimization strategies proposed.

Topics: Azathioprine; Clinical Trials as Topic; Colitis, Ulcerative; Crohn Disease; Disease Susceptibility; Dose-Response Relationship, Drug; Humans; Immunocompromised Host; Immunosuppressive Agents; Infections; Mercaptopurine; Meta-Analysis as Topic; Neoplasms; Prodrugs; Remission Induction; Treatment Outcome

Thiopurine methyltransferase (TPMT) activity shows significant interindividual variation, with approximately 90% of individuals having high (wild-type) activity, 10% with intermediate activity, and 0.3% with low activity. Low and intermediate TPMT activity leads to toxicity from mercaptopurine and the need for dose reduction. Common variants in the TPMT gene have a strong association with mercaptopurine toxicity. However, recent research has shown that genetic contribution to mercaptopurine toxicity is more complex, possibly involving other genes, in particular ITPA, which encodes inosine triphosphate pyrophosphatase.

Topics: Animals; Gene Frequency; Humans; Mercaptopurine; Methyltransferases; Neoplasms; Pharmacogenetics

Thiopurines have diverse clinical applications and their long-term use as anti-rejection drugs in transplant patients has been associated with a significantly increased risk of various types of cancer. Although they are slowly being replaced by a new generation of non-thiopurine immunosuppressants, it is anticipated that their use in the management of inflammatory and autoimmune diseases will continue to increase. Therapy-related cancer will remain a potential consequence of prolonged treatment for these generally non-life-threatening conditions. Understanding how thiopurines contribute to the development of cancer will facilitate clinical decisions about the potential risks to patients of long-term treatment for chronic inflammatory disorders.

Topics: Antineoplastic Agents; Azathioprine; Carcinogens; Cell Survival; Humans; Mercaptopurine; Neoplasms; Purines; Sulfhydryl Compounds; Thioguanine

The Food and Drug Administration (FDA) has approved label changes for two anticancer drugs, 6-mercaptopurine (6-MP) and irinotecan, to include pharmacogenetic testing as a potential means to reduce the rate of severe toxic events. Comprehensive evaluation of the clinical benefit and cost effectiveness of screening strategies with these tests has not been completed. However, the FDA decided that evidence indicates sufficient benefit to warrant informing prescribers, pharmacists and patients of the availability of pharmacogenetic tests and their possible role in the selection and dosing of these anticancer agents. Reviewing the gene-drug-phenotype relationships of 6-MP, irinotecan and 5-fluorouracil reveals properties of these relationships that lead to a clinically useful pharmacogenetic test. Research in the near future should clarify the role of pharmacogenetic testing in reducing the risk of severe toxicity and determine how these same tests might identify a subset of patients who should safely receive higher doses of treatment to derive the same benefit as the rest of the patient population.

Topics: Camptothecin; Dihydrouracil Dehydrogenase (NADP); Genotype; Glucuronosyltransferase; Humans; Irinotecan; Mercaptopurine; Methyltransferases; Neoplasms; Pharmacogenetics; Treatment Outcome

Heterogeneity in patient response to chemotherapy is consistently observed across patient populations. Pharmacogenomics is the study of inherited differences in interindividual drug disposition and effects, with the goal of selecting the optimal drug therapy and dosage for each patient. Pharmacogenomics is especially important for oncology, as severe systemic toxicity and unpredictable efficacy are hallmarks of cancer therapies. In addition, genetic polymorphisms in drug metabolizing enzymes and other molecules are responsible for much of the interindividual differences in the efficacy and toxicity of many chemotherapy agents. This review will discuss clinically relevant examples of gene polymorphisms that influence the outcome of cancer therapy, and whole-genome expression studies using microarray technology that have shown tremendous potential for benefiting cancer pharmacogenomics. The power and utility of the mouse as an experimental system for pharmacogenomic discovery will also be discussed in the context of cancer therapy.

Topics: Animals; Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Camptothecin; Dihydrouracil Dehydrogenase (NADP); Disease Models, Animal; DNA Adducts; DNA Repair; Fluorouracil; Glucuronosyltransferase; Glutathione Transferase; Humans; Irinotecan; Mercaptopurine; Methyltransferases; Neoplasms; Organoplatinum Compounds; Oxidoreductases; Pharmacogenetics; Polymorphism, Genetic; Thymidylate Synthase

There is great heterogeneity in a patient's response to medications, often requiring empirical strategies to define the appropriate drug therapy for each patient. Pharmacogenomics aims to elucidate further the inherited nature of interindividual differences in drug disposition and effects, with the ultimate goal of providing a stronger scientific basis for selecting the optimal drug therapy and dosage for each patient. These genetic insights should also lead to mechanism-based approaches to the discovery and development of new medications. Genetic polymorphisms in drug metabolizing enzymes, transporters, receptors, and other drug targets have been linked to interindividual differences in the efficacy and toxicity of many medications. For example, polymorphism in thiopurine methyltransferase (TPMT) results in altered degradation of the commonly prescribed agent 6-mercaptopurine. This genetic variant has significant clinical implications because patients with functionally relevant homozygous mutations in the TPMT gene experience extreme or fatal toxicity after administration of normal doses of 6-MP. In addition, patients heterozygous for mutations in TPMT require slight dosage reduction of 6-MP and experience a greater degree of systemic toxicity from the agent. This and other examples of genetic polymorphism relevant to the treatment of cancer are highlighted to illustrate the promise and pitfalls of the exciting area of cancer therapeutics, with the potential of providing a stronger scientific basis to optimize drug therapy on the basis of each patient's genetic constitution.

Topics: Antimetabolites, Antineoplastic; DNA Mutational Analysis; DNA, Neoplasm; Genetic Variation; Humans; Medical Oncology; Mercaptopurine; Methyltransferases; Neoplasms; Oligonucleotide Array Sequence Analysis; Patient Care Planning; Pharmacogenetics; Polymorphism, Single Nucleotide

Therapeutic drug monitoring is not routinely used for cytotoxic agents. There are several reasons, but one major drawback is the lack of established therapeutic concentration ranges. Combination chemotherapy makes the establishment of therapeutic ranges for individual drugs difficult, the concentration-effect relationship for a single drug may not be the same as when that drug is used in a drug combination. Pharmacokinetic optimization protocols for many classes of cytotoxic compounds exist in specialized centres, and some of these protocols are now part of large multicentre trials. Nonetheless, methotrexate is the only agent which is routinely monitored in most treatment centres. An additional factor, especially in antimetabolite therapy, is the existence of pharmacogenetic enzymes which play a major role in drug metabolism. Monitoring of therapy could include assay of phenotypic enzyme activities or genotype in addition to, or instead, the more traditional measurement of parent drug or drug metabolites. The cytotoxic activities of mercaptopurine and fluorouracil are regulated by thiopurine methyltransferase (TPMT) and dihydropyrimidine dehydrogenase (DPD), respectively. Lack of TPMT functional activity produces life-threatening mercaptopurine myelotoxicity. Very low DPD activity reduces fluorouracil breakdown producing severe cytotoxicity. These pharmacogenetic enzymes can influence the bioavailability, pharmacokinetics, toxicity and efficacy of their substrate drugs.

Topics: Antimetabolites, Antineoplastic; Drug Interactions; Drug Monitoring; Fluorouracil; Humans; Mercaptopurine; Methotrexate; Neoplasms

The thioguanine derivative, azathioprine, is a prodrug of 6-mercaptopurine that is further metabolized by various enzymes present in the liver and gut. Azathioprine and 6-mercaptopurine have been used in the treatment of inflammatory bowel disease, i.e. ulcerative colitis and Crohn's disease, for more than 30 years. However, widespread use of azathioprine or 6-mercaptopurine in inflammatory bowel disease is of more recent origin, the primary reason being a long-standing debate on the efficacy of these agents in inflammatory bowel disease. Both drugs are slow acting, which is why clinical efficacy cannot be expected until several weeks or even months of treatment have elapsed. Consequently, azathioprine and 6-mercaptopurine have no place as monotherapy in the treatment of acute relapsing inflammatory bowel disease. Today, azathioprine and 6-mercaptopurine are the most commonly used immunomodulatory drugs in the treatment of inflammatory bowel disease. Their clinical effects are probably identical, although their exact mode of action is still unknown. The mode of action of azathioprine is thought to be multifactorial, including conversion to 6-mercaptopurine (which acts as a purine antimetabolite), possible blockade of thiol groups by alkylation, inhibition of several pathways in nucleic acid biosynthesis (preventing proliferation of cells involved in the determination and amplification of the immune response) and damage to DNA through the incorporation of thiopurine analogues. However, 6-thioguanine nucleotides may accumulate in toxic doses in myeloid precursor cells, resulting in life-threatening myelosuppression. Azathioprine and 6-mercaptopurine are further known to alter lymphocyte function, reduce the number of lamina propria plasma cells and affect natural killer cell function. The purpose of this comprehensive review is to suggest guidelines for the application of azathioprine and 6-mercaptopurine in the treatment of inflammatory bowel disease.

Topics: Azathioprine; Clinical Trials as Topic; DNA Damage; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Killer Cells, Natural; Lactation; Lymphocytes; Male; Mercaptopurine; Neoplasms; Practice Guidelines as Topic; Pregnancy; Pregnancy Complications; Risk Factors

Therapeutic drug monitoring is not routinely used for cytotoxic agents. There are several reasons, but one major drawback is the lack of established therapeutic concentration ranges. Combination chemotherapy makes the establishment of therapeutic ranges for individual drugs difficult, the concentration-effect relationship for a single drug may not be the same as that when the drug is used in a drug combination. Pharmacokinetic optimization protocols for many classes of cytotoxic compounds exist in specialized centres, and some of these protocols are now part of large multicentre trials. Nonetheless, methotrexate is the only agent which is routinely monitored in most treatment centres. An additional factor, especially in antimetabolite therapy, is the existence of pharmacogenetic enzymes which play a major role in drug metabolism. Monitoring of therapy could include assay of phenotypic enzyme activities or genotype in addition to, or instead of, the more traditional measurement of parent drug or drug metabolites. The cytotoxic activities of mercaptopurine and fluorouracil are regulated by thiopurine methyltransferase (TPMT) and dihydropyrimidine dehydrogenase (DPD), respectively. Lack of TPMT functional activity produces life-threatening mercaptopurine myelotoxicity. Very low DPD activity reduces fluorouracil breakdown producing severe cytotoxicity. These pharmacogenetic enzymes can influence the bioavailability, pharmacokinetics, toxicity and efficacy of their substrate drugs.

Topics: Antimetabolites, Antineoplastic; Cytarabine; Drug Monitoring; Fluorouracil; Humans; Mercaptopurine; Methotrexate; Neoplasms

Anti-metabolites are among the most important agents used in cancer chemotherapy. Ara-C, the thiopurines and MTX are active drugs for both induction and maintenance chemotherapy of childhood and adult leukaemia, while the new adenosine analogues are active against hairy cell leukaemia, with promising activity against other malignancies such as malignant lymphomas. Methotrexate and 5FU are being used in the treatment of several solid malignancies. Recent advances in the clinical pharmacology of widely used antimetabolites have shown a relationship among dose, plasma concentrations and clearance with the toxicity and anti-tumour activity. Thus, it has been shown that adaptative control of 5FU administration is possible, limiting the toxicity of this drug. Recent advances in the pharmacogenetics of, for example, 6MP and 5FU will possibly enable researchers to identify patients who may have an increased risk of toxicity. For ara-C, some evidence has been obtained to identify populations at risk of no response. In addition, for most anti-metabolites, convincing evidence of their intracellular (intratumour) metabolism has been obtained, thus making it possible to identify patients who are likely to respond to treatment. These studies (eg accumulation of active metabolites such as ara-CTP, thioguanine nucleotides, FdUMP, MTX-polyglutamates; and inhibition of target enzymes such as thymidylate synthase) have made it possible to develop the basis of biochemical modulation--that is, specific manipulation of intracellular metabolism of the drug. It is anticipated that new technical developments in molecular biology, biochemistry, cell biology and immunology will make it possible to improve the identification of resistant patients in order to modulate specifically drug metabolism in the tumour cells. Biochemical modulation has been successful in achieving significant improvements in treatment and currently is a keystone in cancer chemotherapy. Together with the development of promising new anti-metabolites, biochemical modulation (with other drugs, biologicals) will be a major strategy for the future.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Arabinofuranosylcytosine Triphosphate; Cytarabine; Fluorouracil; Humans; Mercaptopurine; Methotrexate; Neoplasms

Maturation of physiologic process which govern the disposition of pharmacologic agents can yield significant changes in absorption, distribution, metabolism, and elimination of drugs in neonates, infants and children. However, there are very little data concerning the disposition of anticancer drugs in young children. Pharmacokinetic data for six anticancer agents were compared in infants less than 1 year of age and children greater than 1 year of age treated at St Jude Children's Research Hospital. No pharmacokinetic data were available for infants less than 2 months of age. Median methotrexate clearance tended to be lower in four infants (0.26-0.99 years) vs 108 children (1-19 years): 80 vs 103 ml min-1 m-2, respectively (P = 0.01). There was no difference in the median 42 h methotrexate concentration. Teniposide systemic clearance and terminal half-life and cytarabine systemic clearance were not different between the two groups. There was no significant difference in etoposide systemic clearance when normalised to body surface area (ml min-1 m-2), however a significantly lower systemic clearance relative to body weight (ml min-1 kg-1) was observed in two infants, 0.5 to 1 year of age, vs 23 children, 3-18 years of age. Doxorubicin systemic clearance was not significantly different between the two groups when systemic clearance was expressed in ml min-1 kg-1. However, there was a trend toward a lower rate of systemic clearance in ml min-1 m-2 in infants.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Age Factors; Antineoplastic Agents; Blood Proteins; Child; Child, Preschool; Doxorubicin; Etoposide; Humans; Infant; Infant, Newborn; Liver; Mercaptopurine; Methotrexate; Neoplasms; Nervous System; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Teniposide

The proposal is advanced that anti-cancer drugs generally function by charge transfer resulting in formation of toxic oxy radicals which destroy the neoplasm. Electrochemical studies were performed with some of the main types of agents: iminium ions (adenine iminium from alkylating species, iminium metabolite of 6-mercaptopurine, nitidine, other polynuclear iminiums) and metal complexes (Pt(II)diaquodiammine-guanosine, copper salicylaldoximes). Reduction potentials ranged from -0.4 to -1.2 V. Literature data for quinones are presented and radiation is discussed. Based on the theoretical framework, a rationale is offered for the carcinogen-anti-cancer paradox and the role of antioxidants.

Topics: Alkylation; Antineoplastic Agents; Antioxidants; DNA; Ellipticines; Free Radicals; Mercaptopurine; Metals; Neoplasms; Oxygen; Quinolines; Quinones

The narrow therapeutic index and potentially life-threatening toxicities of the antineoplastic agents require a clear understanding of their toxicologic and pharmacologic properties, particularly in infants and children. This article reviews the literature published in the last five years on pediatric cancer chemotherapy. It begins with an overview of new concepts in antineoplastic therapy and then summarizes each of the main drugs used to treat the cancer of infants and children.

Topics: Adolescent; Antineoplastic Agents; Asparaginase; Bleomycin; Catheters, Indwelling; Child; Child, Preschool; Cisplatin; Cyclophosphamide; Cytarabine; Dacarbazine; Dactinomycin; Daunorubicin; Doxorubicin; Humans; Infant; Infant, Newborn; Infusions, Parenteral; Mercaptopurine; Methotrexate; Neoplasms; Nitrosourea Compounds; Thioguanine; Vinblastine; Vincristine

Topics: Acyclovir; Allopurinol; Animals; Drug Therapy; Folic Acid Antagonists; Herpes Simplex; Herpes Zoster; Humans; Leishmania; Mercaptopurine; Neoplasms; Nucleic Acid Synthesis Inhibitors; Recurrence; Species Specificity

Topics: Animals; Azathioprine; Biotransformation; DNA; DNA Replication; Humans; Immune System Diseases; Mercaptopurine; Neoplasms; Structure-Activity Relationship

Glutathione, as the chief nonprotein intracellular sulfhydryl, affects the efficacy and interactions of a variety of antineoplastic interventions, mainly through nucleophilic thioether formation or oxidation-reduction reactions. Thus, glutathione plays a role in the detoxification and repair of cellular injury by such diverse agents as mechlorethamine, melphalan, cyclophosphamide, nitrosoureas, 6-thiopurine, 4'-(9-acridinylamino)methanesulfon-m-anisidide, the quinone antibiotics (including Adriamycin, daunorubicin, and mitomycin C), the sesquiterpene lactones (such as vernolepin), and other sulfhydryl-reactive diterpenes (like jatrophone). Glutathione may play a similar role in host and tumor cell responses to radiation, hyperthermia, and the reactive reduction products of oxygen secreted by inflammatory cells. Further, glutathione participates in the formation of toxic metabolites of such chemotherapeutics as azathioprine and bleomycin and may affect the cellular uptake of other agents, such as methotrexate. It seems likely that alterations in glutathione metabolism of tumor or host as a result of one therapeutic intervention may affect the outcome of concurrent treatments. Knowledge of these interactions may be useful in designing combination therapy for neoplastic disease.

Topics: Aminoacridines; Amsacrine; Animals; Antineoplastic Agents; Biological Transport; Carmustine; Cyclophosphamide; Cytochrome P-450 Enzyme System; Glutathione; Humans; Mechlorethamine; Melphalan; Mercaptopurine; Mice; Neoplasms; Neoplasms, Experimental

A review of experimental studies of chemotherapeutic agents and wound healing has demonstrated impairment of healing by a wide variety of agents. The extent of impairment by several agents (corticosteroids, Adriamycin, methotrexate, and cyclophosphamide) is dependent upon the interval between administration and wounding. If given within three to four days of wounding significant impairment results, but beyond that interval, impairment is minimal. Studies in animals with some agents (adriamycin, nitrogen mustard, cyclophosphamide, and methotrexate) have shown a dose-dependent impairment of healing, but extrapolation of these doses to regimens employed in man is impossible. Information regarding complications of chemotherapeutic agents in wound healing in man is available from adjuvant studies. No increased frequency of complications from nitrogen mustard, thio-TEPA, or cyclophosphamide occurred, even when these agents were given in the immediate perioperative period. Increased wound complications occurred with 5-fluorouracil when a 60 mg/kg dose was begun seven days after surgery but not when it was begun 14 days after surgery. These results stress the need for continued attention to wound complication occurring in adjuvant studies, and suggest that delay of treatment until seven days after surgery should produce minimal impairment.

Topics: Adrenal Cortex Hormones; Anemia; Animals; Antineoplastic Agents; Azathioprine; Collagen; Cyclophosphamide; Dose-Response Relationship, Drug; Doxorubicin; Fluorouracil; Humans; Leukopenia; Mechlorethamine; Mercaptopurine; Methotrexate; Neoplasms; Tensile Strength; Thiotepa; Time Factors; Wound Healing

Topics: Allopurinol; Drug Interactions; Drug Resistance; Humans; Leukemia; Mercaptopurine; Neoplasms; Purines; Thioguanine

Topics: Adrenal Cortex Hormones; Alkylating Agents; Animals; Antineoplastic Agents; Asparaginase; Choriocarcinoma; Dactinomycin; Female; Folic Acid Antagonists; History, 19th Century; History, 20th Century; Humans; Leukemia, Lymphoid; Lymphoma; Mercaptopurine; Neoplasms; Pregnancy

Topics: Animals; BCG Vaccine; Cyclophosphamide; Cytarabine; Daunorubicin; Doxorubicin; Drug Therapy, Combination; Fluorouracil; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Immunotherapy; Levamisole; Mercaptopurine; Methotrexate; Mice; Neoplasms; Propionibacterium acnes; Vinca Alkaloids

Although cytotoxic immunosuppressive agents play an unquestionably useful role in treating many neoplastic and non-neoplastic disorders, there is accumulating evidence that the toxicity associated with their use is considerable. The therapeutic successes obtained with antitumor agents have led to increases in the life span of cancer patients, but have also provided the opportunity for this toxicity to become manifest. A search of the available literature was carried out, with emphasis on cases in which a malignancy developed in patients following chemotherapy for either neoplastic or non-neoplastic (e.g., renal transplantation, psoriasis) conditions; particular focus was given to the incidence of acute myelogenous leukemia in various groups of Hodgkin's disease and multiple myeloma patients. That patients with nonmalignant conditions treated with cytotoxic immunosuppressive agents are also at increased risk of developing a malignancy raises the possibility that these agents may have oncogenic potential. Therefore, one may be faced with the paradox that the patients benefiting most from chemotherapy may be at highest risk of suffering its consequences.

Topics: Alkylating Agents; Animals; Antineoplastic Agents; Azathioprine; Burkitt Lymphoma; Choriocarcinoma; Cyclophosphamide; Dactinomycin; Female; Hodgkin Disease; Humans; Immunosuppressive Agents; Kidney Neoplasms; Leukemia, Myeloid, Acute; Lymphoma; Mechlorethamine; Melphalan; Mercaptopurine; Methotrexate; Mice; Multiple Myeloma; Neoplasms; Prednisone; Pregnancy; Procarbazine; Time Factors; Vincristine

In combination chemotherapy, the type of drug interactions can be divided into three broad categories: 1) combinations based on cooperative effects of active drugs; 2) combinations in which the effectiveness of an active drug is increased by the concurrent administration of an inactive agent; and 3) combination of an active drug with an agent capable of selectively reversing the toxicity of the first drug. Many concepts have been proposed to explain the synergistic interaction between two active drugs at the level of the target cell. These include multiple inhibition of a single enzyme, enhanced activation, decreased inactivation, increased drug uptake, sequential blockade, concurrent inhibition, complimentary inhibition, and concerted inhibition. The therapeutic advantage of combination chemotherapy may reside in the whole organism, reflecting increased bioavailability of drug, reduced dose-limiting toxicity or reduced impairment of host defenses; it may reside in the tumor cells, reflecting the multiple molecular mechanisms of interaction mentioned above. Examples discussed include among others methotrexate plus citrovorum factor, thymidine or allopurinol, araC plus tetrahydrouridine and 3-deazauridine plus testosterone.

Topics: Animals; Antineoplastic Agents; Cyclophosphamide; Cytarabine; Daunorubicin; Drug Antagonism; Drug Interactions; Drug Synergism; Drug Therapy, Combination; Humans; Leucovorin; Mercaptopurine; Methotrexate; Neoplasms; Neoplasms, Experimental; Uridine

Topics: Abnormalities, Drug-Induced; Adolescent; Adult; Antineoplastic Agents; Busulfan; Carcinogens; Central Nervous System Diseases; Chemical and Drug Induced Liver Injury; Child; Female; Heart Diseases; Humans; Lung Diseases; Male; Menstruation Disturbances; Mercaptopurine; Methotrexate; Neoplasms; Neoplasms, Radiation-Induced; Pregnancy; Radiotherapy; Urinary Bladder Diseases

Topics: Animals; Antineoplastic Agents; Binding Sites; Chickens; Cyclophosphamide; Cytarabine; Fluorouracil; Guinea Pigs; Humans; Immunity; Immunity, Cellular; Immunosuppressive Agents; Leucovorin; Male; Mercaptopurine; Methotrexate; Mice; Neoplasms; Piperazines; Rats; Stimulation, Chemical

Cytotoxic drugs, which are widely used as immunosuppressive and antiinflammatory agents in patients with neoplastic conditions, and cancer chemotherapy preparations, are of long-range concern due to the problem of cumulative organ toxicity which is not manifested until damage is extensive. These considerations have arisen because of their widespread use in recent years. Those involved in hepatic toxicity are the antimetabolites methotrexate and 6-mercaptopurine. Bisulfin, bleomycin, and methotrexate have been linked to pulmonary toxicity. Daunomycin and adriamycin, used as anticarcinogens, are examined for their cardiac toxicity. Cyclophosphamide and streptozotocin affect the urinary tract. These drugs have specific toxic effects on fertility in both males, through its disruption of the testicular function, and in females, for ovarian disruptions. Antifolics, 6-mercaptopurine, azathioprine, and alkylating agents, used for therapy in pregnant women, particularly in the first 4 months, are linked to the appearance of fetal abnormalities. The process of carcinogenesis is examined for clues to possible chemotherapy-related 2nd tumors, which appear during the course of treatment.

Topics: Alkylating Agents; Antineoplastic Agents; Azathioprine; Bleomycin; Busulfan; Carcinogens; Chemical and Drug Induced Liver Injury; Daunorubicin; Doxorubicin; Female; Fetus; Folic Acid Antagonists; Follow-Up Studies; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Infertility, Female; Infertility, Male; Liver; Lung Diseases; Male; Mercaptopurine; Methotrexate; Myocarditis; Neoplasms; Ovary; Pregnancy; Procarbazine; Streptozocin; Testis; Urologic Diseases

Topics: Antineoplastic Agents; Asparaginase; Cell Division; Chlorambucil; Cyclophosphamide; Cytarabine; Drug Therapy, Combination; Fluorouracil; Folic Acid Antagonists; Humans; Melphalan; Mercaptopurine; Methotrexate; Neoplasms; Triaziquone; Triethylenephosphoramide; Vincristine

Topics: Age Factors; Breast Neoplasms; Cell Movement; Clinical Enzyme Tests; Colonic Neoplasms; Cytarabine; Diagnosis, Differential; Doxorubicin; Drug Combinations; Drug Evaluation; Drug Evaluation, Preclinical; Fluorouracil; Humans; Kinetics; Leukemia; Mercaptopurine; Methods; Methotrexate; Models, Chemical; Neoplasms; Prognosis; Sarcoma; Testosterone; Thioguanine

Topics: Animals; Antineoplastic Agents; Asparaginase; Azathioprine; Bleomycin; Cytarabine; Dactinomycin; Daunorubicin; Dimethylamines; Doxorubicin; Floxuridine; Fluorouracil; Humans; Hydroxyurea; Imidazoles; Mercaptopurine; Mitomycins; Mitotane; Neoplasms; Nitrosourea Compounds; Pipobroman; Procarbazine; Streptonigrin; Streptozocin; Thioguanine; Triazenes; Triazines; Vinblastine; Vincristine

Topics: Abnormalities, Drug-Induced; Alkylating Agents; Allopurinol; Alopecia; Antimetabolites; Antineoplastic Agents; Chemotherapy, Cancer, Regional Perfusion; Cyclophosphamide; Drug Synergism; Female; Fetus; Humans; Kidney Calculi; Kidney Diseases; Kidney Tubules; Mechlorethamine; Mercaptopurine; Neoplasms; Pregnancy; Pregnancy Complications; Uric Acid; Vincristine

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Bone Marrow; Bone Marrow Cells; Cell Division; Cyclophosphamide; Cytarabine; Female; Fluorouracil; Humans; Leukemia L1210; Leukemia, Lymphoid; Lymphoma; Melphalan; Mercaptopurine; Methotrexate; Mice; Multiple Myeloma; Neoplasms; Nitrogen Mustard Compounds; Prednisone; Pregnancy; Time Factors; Trophoblastic Neoplasms; Vinblastine

Topics: Antineoplastic Agents; Child; Fluorouracil; Forecasting; Humans; Leukemia; Mercaptopurine; Methotrexate; Neoplasms; Prognosis

Topics: Allopurinol; Animals; Antimetabolites; Azathioprine; Cell Division; Chemical Phenomena; Chemistry; Cytarabine; DNA, Neoplasm; Fluorouracil; Folic Acid Antagonists; Humans; Leukemia; Mercaptopurine; Methotrexate; Neoplasms; Pyrimidines; Thioguanine

Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Agents; Asparaginase; Azaserine; Cell Division; Clinical Trials as Topic; Cyclophosphamide; Cytarabine; Disease Models, Animal; Drug Combinations; Humans; Kinetics; Leukemia L1210; Leukemia, Experimental; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Mercaptopurine; Methotrexate; Neoplasms; Prednisone; Remission, Spontaneous; RNA, Neoplasm; Vincristine

Topics: Alkylating Agents; Animals; Antibiotics, Antineoplastic; Antimetabolites; Antineoplastic Agents; Busulfan; Fluorouracil; Hemangiosarcoma; Mercaptopurine; Mitomycins; Neoplasms; Neoplasms, Experimental; Podophyllin; Rats; Sarcoma, Experimental; Thiotepa; Vinblastine

Topics: Alkaloids; Animals; Antibiotics, Antineoplastic; Antineoplastic Agents; Cell Nucleus; Cell Transformation, Neoplastic; Colchicine; Colchicum; DNA; Drug Synergism; Glutamine; Glycolysis; Humans; Leukemia; Mercaptopurine; Methotrexate; Mitosis; Neoplasms; Plant Extracts; Plants, Medicinal; Plants, Toxic; Podophyllum; Prednisone; Purines; Pyrimidines; RNA; Steroids; Vincristine

Topics: Animals; Antibody Formation; Bacteria; Bone Marrow; Drug Resistance, Microbial; Eukaryota; Gout; Humans; Intestinal Mucosa; Mercaptopurine; Neoplasms; Nephrotic Syndrome; Nucleic Acids; Nucleotidases; Oxidoreductases; Phosphotransferases; Platelet Adhesiveness; Protein Biosynthesis; Purines; Rats; Transferases; Viruses

Topics: Adrenal Cortex Hormones; Adult; Allopurinol; Autoimmune Diseases; Azathioprine; Bone Diseases; Diabetes Mellitus; Drug Synergism; Duodenal Ulcer; Embolism, Fat; Glomerulonephritis; Histocompatibility; Humans; Hypertension, Renal; Immunosuppressive Agents; Infections; Kidney Glomerulus; Kidney Transplantation; Malabsorption Syndromes; Male; Mercaptopurine; Neoplasm Transplantation; Neoplasms; Obesity; Osteoporosis; Pancreatitis; Peptic Ulcer Hemorrhage; Phenylbutazone; Postoperative Complications; Proteinuria; Transplantation, Homologous

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; Chloroquine; Cyclophosphamide; Cytarabine; Drug Synergism; Fluorouracil; Humans; Japan; Leukemia; Lymphoma; Mercaptopurine; Mitomycins; Neoplasms; Podophyllin; Prednisolone; Thiotepa; Vincristine; Vitamin K 1

Topics: Allopurinol; Animals; Antimetabolites; Azathioprine; Binding Sites; Drug Therapy; Enzyme Inhibitors; Enzyme Precursors; Folic Acid; Folic Acid Antagonists; Humans; Lactobacillus; Leukemia, Myeloid; Liver; Mercaptopurine; Methotrexate; Mice; Molecular Weight; Neoplasms; Nucleic Acids; Proteus; Purines; Research; Species Specificity; Thymine; Transferases; Uric Acid; Xanthine Oxidase

Topics: Alkylating Agents; Aminopterin; Animals; Antimetabolites; Antineoplastic Agents; Busulfan; Chlorambucil; Choriocarcinoma; Colchicine; Female; Fetal Death; Folic Acid Antagonists; Gestational Age; Humans; Mercaptopurine; Methotrexate; Neoplasms; Nitrogen Mustard Compounds; Pregnancy; Pregnancy Complications; Urethane; Vinblastine

Topics: Adrenal Cortex Hormones; Alkaloids; Androgens; Anti-Bacterial Agents; Cyclophosphamide; DNA; DNA, Neoplasm; Estrogens; Fluorouracil; Folic Acid Antagonists; Humans; Hydroxyurea; Mercaptopurine; Neoplasms; Nucleic Acids; Protein Biosynthesis; Ribosomes; RNA, Messenger; RNA, Neoplasm; Vinblastine

Topics: Agammaglobulinemia; Antibody Formation; Biomedical Research; Child; Genetics, Medical; Hodgkin Disease; Humans; Immune Tolerance; Infant, Newborn; Lymph Nodes; Lymphoid Tissue; Mercaptopurine; Neoplasms; Neoplasms, Experimental; Radiation Effects; Research; Skin Transplantation; Thymectomy; Thymus Gland; Transplantation; Transplantation Immunology

Topics: Animals; Anti-Bacterial Agents; Antineoplastic Agents; Azaguanine; Azaserine; Carcinoma, Ehrlich Tumor; DNA; DNA, Neoplasm; Floxuridine; Fluorouracil; Folic Acid; Glutamine; Leukemia L1210; Mercaptopurine; Methotrexate; Mitomycin; Neoplasms; Neoplasms, Experimental; Pharmacology; Purines; Puromycin; Pyrimidines; Research; RNA; RNA, Neoplasm; Thioguanine; Thiouracil

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Clinical Trials as Topic; Cyclophosphamide; Female; Fluorouracil; Humans; Male; Mercaptopurine; Methotrexate; Middle Aged; Neoplasms; Procarbazine; Vinblastine

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; Carcinoma, Bronchogenic; Carcinoma, Squamous Cell; Clinical Trials as Topic; Cyclophosphamide; Drug Synergism; Female; Fluorouracil; History, 16th Century; Humans; Hydrazines; Injections, Intravenous; Laryngeal Neoplasms; Male; Mechlorethamine; Mercaptopurine; Methotrexate; Neoplasm Metastasis; Neoplasms; Prognosis; Time Factors; Tongue Neoplasms; Vinblastine

Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Agents; Asparaginase; Azaserine; Cell Division; Clinical Trials as Topic; Cyclophosphamide; Cytarabine; Disease Models, Animal; Drug Combinations; Humans; Kinetics; Leukemia L1210; Leukemia, Experimental; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Mercaptopurine; Methotrexate; Neoplasms; Prednisone; Remission, Spontaneous; RNA, Neoplasm; Vincristine

Topics: Adenocarcinoma; Anemia; Bone Marrow Diseases; Carcinoma, Squamous Cell; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Colonic Neoplasms; Humans; Leukopenia; Lung Neoplasms; Mercaptopurine; Nausea; Neoplasms; Rectal Neoplasms; Stomach Neoplasms; Thrombocytopenia; Vomiting

Topics: Breast Neoplasms; Clinical Trials as Topic; Gastrointestinal Neoplasms; Humans; Lung Neoplasms; Lymphoma; Melanoma; Mercaptopurine; Neoplasms

Topics: Antineoplastic Agents; Clinical Trials as Topic; Humans; Injections, Intravenous; Mercaptopurine; Neoplasms

Antibody inhibitors that block PD-1/PD-L1 interaction have been approved for oncological clinics, yielding impressive treatment effects. Small molecules inhibiting PD-1 signalling are at various stages of development, given that small molecular drugs are expected to outperform protein drugs in several ways. Currently, a significant portion of these small molecular inhibitors achieve this purpose by binding to a limited region of the PD-L1 protein, thereby limiting the choice of chemical structures. Alternative strategies for developing small-molecular PD-1 inhibitors are urgently needed to broaden the choice of chemical structures. Here, we report that 6-mercaptopurine (6-MP) inhibits PD-1 signalling, activates T cell function in vitro and in vivo and shrinks tumours by activating cytotoxic T cells. Mechanistically, 6-MP potently inhibited PD-1 signalling by blocking the recruitment of SHP2 by PD-1. Considering that 6-MP is a chemotherapeutic agent already approved by the FDA for childhood leukaemia, our work revealed a novel anti-tumour mechanism for this drug and suggests that 6-MP warrants further clinical evaluation for other tumour types.

Topics: B7-H1 Antigen; Child; Humans; Immunotherapy; Mercaptopurine; Neoplasms; Programmed Cell Death 1 Receptor; Signal Transduction; T-Lymphocytes

A 36-year-old woman presented to the emergency department with a 1-day history of purulent perianal and vulvar discharge. She had a 25-year history of Crohn's disease (CD), and 13 years prior had received a total colectomy with end ileostomy. She had vulvar biopsies 5 years prior to presentation, demonstrating noncaseating granulomas consistent with metastatic Crohn's disease (MCD). Throughout the course of her disease, she had a failed treatment with adalimumab, certolizumab, methotrexate, and 6-mercaptopurine. She had received a radical vulvectomy 1 year prior to presenting to control recurrent vulvar abscesses and MCD while receiving monthly subcutaneous infliximab 10 mg/kg body weight. Dermatology was consulted at presentation, and the physical examination revealed tender, linear ulcerations with a granulated appearance and depigmentation on the natal cleft and vulva (Figures 1 and 2). Computerized tomography (CT) scan of the abdomen and pelvis indicated thickening of soft tissue without evidence of abscesses, fluid collection, or fistulae. Given the distribution and morphology of lesions with a history of biopsy-proven MCD, the patient was diagnosed with a flare of MCD.

Topics: Abscess; Adult; Crohn Disease; Female; Humans; Infliximab; Mercaptopurine; Methotrexate; Neoplasms; Recurrence

The aim of this study was to describe the long-term health outcomes of children born to mothers with inflammatory bowel disease (IBD) and to assess the impact of maternal IBD medication use on these outcomes.. We performed a multicentre retrospective study in The Netherlands. Women with IBD who gave birth between 1999 and 2018 were enrolled from 20 participating hospitals. Information regarding disease characteristics, medication use, lifestyle, pregnancy outcomes and long-term health outcomes of children was retrieved from mothers and medical charts. After consent of both parents, outcomes until 5 years were also collected from general practitioners. Our primary aim was to assess infection rate and our secondary aims were to assess adverse reactions to vaccinations, growth, autoimmune diseases and malignancies.. We included 1000 children born to 626 mothers (381 (61%) Crohn's disease, 225 (36%) ulcerative colitis and 20 (3%) IBD unclassified). In total, 196 (20%) had intrauterine exposure to anti-tumour necrosis factor-α (anti-TNF-α) (60 with concomitant thiopurine) and 240 (24%) were exposed to thiopurine monotherapy. The 564 children (56%) not exposed to anti-TNF-α and/or thiopurine served as control group. There was no association between adverse long-term health outcomes and in utero exposure to IBD treatment. We did find an increased rate of intrahepatic cholestasis of pregnancy (ICP) in case thiopurine was used during the pregnancy without affecting birth outcomes and long-term health outcomes of children. All outcomes correspond with the general age-adjusted population.. In our study, we found no association between in utero exposure to anti-TNF-α and/or thiopurine and the long-term outcomes antibiotic-treated infections, severe infections needing hospital admission, adverse reactions to vaccinations, growth failure, autoimmune diseases and malignancies.

Topics: Adalimumab; Adult; Anti-Bacterial Agents; Autoimmune Diseases; Cesarean Section; Child Development; Child, Preschool; Congenital Abnormalities; Drug Prescriptions; Drug Therapy, Combination; Female; Gastrointestinal Agents; Humans; Infant; Infant, Newborn; Infant, Small for Gestational Age; Infections; Inflammatory Bowel Diseases; Infliximab; Mercaptopurine; Neoplasms; Netherlands; Patient Admission; Pregnancy; Pregnancy Complications; Premature Birth; Prenatal Exposure Delayed Effects; Retrospective Studies; Tumor Necrosis Factor Inhibitors; Vaccines

Topics: Click Chemistry; Delayed-Action Preparations; Doxorubicin; Drug Carriers; HeLa Cells; HL-60 Cells; Humans; Mercaptopurine; Neoplasms; Prodrugs

The clinical applications of anticancer drugs are restricted due to the incomplete delivery to the cancerous tissue and the numerous drug resistance mechanisms involved in malignant cells. In this regard, stimuli-responsive nanomaterials offer a promising prospect to deal with these concerns. In the present study, ternary responsive hybrid gold/nanogels (Au/NGs) were synthesized as a new nanoplatform to simultaneously carry two anticancer drugs, i.e., doxorubicin (DOX) and 6-mercaptopurine (MP). For this purpose, these drugs were successfully loaded (the loading capacity of 23% and 11%, respectively) into the hybrid Au/NGs by electrostatic interaction (DOX) and AuS bonds (MP). The triggered drug release ability of hybrid Au/NGs was assessed by comparing the environments of simulated physiological and tumor tissue. The incorporation of disulfide bond linkers, pH sensitive, and thermosensitive polymeric segments endowed the NGs with an excellent property in reducing acidic and hyperthermia environments, which greatly facilitates drug release in tumor cells. Intracellular tracking of DOX@MP-Au/NGs confirmed efficient accumulation and cellular uptake of developed NGs and the cytotoxicity studies showed a pronounced tumor inhibition compared with free DOX@MP. It was concluded that the new ternary-responsive NGs have great potential for co-delivery of DOX and MP and can be used in efficient cancer therapy.

Topics: Doxorubicin; Drug Delivery Systems; Gels; Gold; Humans; MCF-7 Cells; Mercaptopurine; Nanoparticles; Neoplasms; Polyethylene Glycols

Stimuli-responsive nanomaterials have been receiving much attention as drug delivery carriers, however understanding of multi-drug release from the carriers for efficient therapeutics is highly challenging. Here, we report a novel nanosystem, Janus particle Dox-CMR-MS/Au-6MP (Dox: doxorubicin, CMR: 7-hydroxycoumarin-3-carboxylate, MS: mesoporous silica, Au: gold, 6MP: 6-mercaptopurine) with opposing MS and Au faces, which can monitor intracellular dual-drug (Dox and 6MP) controlled release in real time based on fluorescence resonance energy transfer (FRET) and surface-enhanced Raman scattering (SERS). The FRET acceptor Dox is attached to CMR (as a FRET donor) conjugated MS with a pH-responsive linker hydrazone, and 6MP is conjugated to the Au surface through the gold-thiol interaction. As the Janus nanoparticle enters into tumor cells, the breakage of the hydrazone bond in an acidic environment and the substitution of glutathione (GSH) overexpressed in cancer cells give rise to the release of Dox and 6MP, respectively. Thus, the change of the CMR fluorescence signal and the SERS decrease of 6MP can be used to monitor the dual-drug release within living cells in real time. In addition, this work demonstrates the enhanced anticancer effect of the designed dual-drug loaded nanosystem. Therefore, the current study may provide new perspectives for the real-time study of intelligent multi-drug delivery and release, as well as cellular responses to drug treatment.

Topics: Cell Survival; Doxorubicin; Drug Carriers; Drug Delivery Systems; Drug Liberation; Fluorescence Resonance Energy Transfer; Glutathione; Gold; HeLa Cells; Humans; Hydrazones; Hydrogen-Ion Concentration; Mercaptopurine; Nanoparticles; Nanotechnology; Neoplasms; Scattering, Radiation; Spectrum Analysis, Raman; Umbelliferones

6-Mercaptopurine (6MP) is a well-known purine antimetabolite used to treat childhood acute lymphoblastic leukemia and other diseases. Cancer cells as compared to normal cells are under increased oxidative stress and show high copper level. These differences between cancer cells and normal cells can be targeted to develop effective cancer therapy. Pro-oxidant property of 6MP in the presence of metal ions is not well documented. Redox cycling of Cu(II) to Cu(I) was found to be efficiently mediated by 6MP. We have performed a series of in vitro experiments to demonstrate the pro-oxidant property of 6MP in the presence of Cu(II). Studies on human lymphocytes confirmed the DNA damaging ability of 6MP in the presence of Cu(II). Since 6MP possesses DNA damaging ability by producing reactive oxygen species (ROS) in the presence of Cu(II), it may also possess apoptosis-inducing activity by involving endogenous copper ions. Essentially, this would be an alternative and copper-dependent pathway for anticancer activity of 6MP.

Topics: Antineoplastic Agents; Apoptosis; Copper; DNA Damage; Humans; Lymphocytes; Mercaptopurine; Neoplasms; Oxidation-Reduction; Oxidative Stress; Reactive Oxygen Species

Topics: Accidents; Antimetabolites, Antineoplastic; Child, Preschool; Humans; Male; Mercaptopurine; Neoplasms

6-Mercaptopurine (6-MP) is one of the key drugs in the treatment of many pediatric cancers, auto immune diseases and inflammatory bowel disease. 6-MP is a prodrug, converted to an active metabolite 6-thioguanine nucleotide (6-TGN) through enzymatic reaction involving thiopurine methyltransferase (TPMT). Pharmacogenomic variation observed in the TPMT enzyme produces a significant variation in drug response among the patient population. Despite 6-MP's widespread use and observed variation in treatment response, efforts at quantitative optimization of dose regimens for individual patients are limited. In addition, research efforts devoted on pharmacogenomics to predict clinical responses are proving far from ideal. In this work, we present a Bayesian population modeling approach to develop a pharmacological model for 6-MP metabolism in humans. In the face of scarcity of data in clinical settings, a global sensitivity analysis based model reduction approach is used to minimize the parameter space. For accurate estimation of sensitive parameters, robust optimal experimental design based on D-optimality criteria was exploited. With the patient-specific model, a model predictive control algorithm is used to optimize the dose scheduling with the objective of maintaining the 6-TGN concentration within its therapeutic window. More importantly, for the first time, we show how the incorporation of information from different levels of biological chain-of response (i.e. gene expression-enzyme phenotype-drug phenotype) plays a critical role in determining the uncertainty in predicting therapeutic target. The model and the control approach can be utilized in the clinical setting to individualize 6-MP dosing based on the patient's ability to metabolize the drug instead of the traditional standard-dose-for-all approach.

Topics: Antineoplastic Agents; Bayes Theorem; Genetic Association Studies; Guanine Nucleotides; Humans; Immunosuppressive Agents; Mercaptopurine; Models, Biological; Neoplasms; Precision Medicine; Prodrugs; Thionucleotides

A major tenet of cancer therapeutics is that combinations of anticancer agents with different mechanisms of action and different toxicities may be effective treatment regimens. Evaluation of additivity/synergy in cell culture may be used to identify drug combination opportunities and to assess risk of additive/synergistic toxicity. The combination of 6-mercaptopurine and dasatinib was assessed for additivity/synergy using the combination index (CI) method and a response surface method in six human tumor cell lines including MCF-7 and MDA-MB‑468 breast cancer, NCI-H23 and NCI-H460 non‑small cell lung cancer, and A498 and 786-O renal cell cancer, based on two experimental end‑points: ATP content and colony formation. Clonal colony formation by human bone marrow CFU-GM was used to assess risk of enhanced toxicity. The concentration ranges tested for each drug were selected to encompass the clinical Cmax concentrations. The combination regimens were found to be additive to sub‑additive by both methods of data analysis, but synergy was not detected. The non-small cell lung cancer cell lines were the most responsive among the tumor lines tested and the renal cell carcinoma lines were the least responsive. The bone marrows CFU-GM were more sensitive to the combination regimens than were the tumor cell lines. Based upon these data, it appears that the possibility of enhanced efficacy from combining 6-mercaptopurine (6-MP) and dasatinib would be associated with increased risk of severe bone marrow toxicity, so the combination is unlikely to provide a therapeutic advantage for treating solid tumor patients where adequate bone marrow function must be preserved.

Topics: Antineoplastic Combined Chemotherapy Protocols; Dasatinib; Drug Synergism; Humans; In Vitro Techniques; MCF-7 Cells; Mercaptopurine; Neoplasms; Pyrimidines; Thiazoles; Tumor Stem Cell Assay

Mesoporous silica nanoparticles with amino and thiol groups (MSNSN) were prepared and covalently modified with methotrexate and 6-mercaptopurine to form 6-MP-MSNSN-MTX. In the presence of DTT, 6-MP-MSNSN-MTX gradually releases 6-MP. In rat plasma, 6-MP-MSNSN-MTX effectively inhibits the metabolic deactivation of 6-MP and MTX. 6-MP-MSNSN-MTX could be an agent for long-acting chemotherapy.

Topics: Cell Proliferation; Dithiothreitol; Endocytosis; Humans; K562 Cells; Mercaptopurine; Metal Nanoparticles; Methotrexate; Neoplasms; Porosity; Silicon Dioxide; Surface Properties

To investigate the incidence of neoplasms in inflammatory bowel disease (IBD) patients and the potential causative role of thiopurines.. We performed an observational descriptive study comparing the incidence of malignancies in IBD patients treated with thiopurines and patients not treated with these drugs. We included 812 patients which were divided in two groups depending on whether they have received thiopurines or not. We have studied basal characteristics of both groups (age when the disease was diagnosed, sex, type of IBD, etc.) and treatments received (Azathioprine, mercaptopurine, infliximab, adalimumab or other immunomodulators), as well as neoplasms incidence. Univariate analysis was performed with the student t test, χ(2) test or Wilcoxon exact test as appropriate. A logistic regression analysis was performed as multivariate analysis. Statistical significance was establish at P values of less than 0.05, and 95%CI were used for the odds ratios.. Among 812 patients included, 429 (52.83%) have received thiopurines: 79.5% azathioprine, 14% mercaptopurine and 6.5% both drugs. 44.76% of patients treated with thiopurines and 46, 48% of patients who did not receive this treatment were women (P > 0.05). The proportion of ulcerative colitis patients treated with thiopurines was 30.3% compare to 66. 67% of patients not treated (P < 0.001). Mean azathioprine dose was 123.79 ± 36.5 mg/d (range: 50-250 mg/d), mean usage time was 72.16 ± 55.7 mo (range: 1-300 mo) and the accumulated dose along this time was 274.32 ± 233.5 g (1.5-1350 g). With respect to mercaptopurine, mean dose was 74.7 ± 23.9 mg/d (range: 25-150 mg/d), mean usage time of 23.37 ± 27.6 mo (range: 1-118 mo), and the accumulated dose along this time was 52.2 ± 63.5 g (range: 1.5-243 g). Thiopurine S-methyltransferase activity was tested in 66% of patients treated with thiopurines, among which 98.2% had an intermediate or high activity. Among the patients treated with thiopurines, 27.27% (112 patients) and 11.66% (50 patients) received treatment with Infliximab and Adalimumab respectively, but only 1.83% (7 patients) and 0.78% (3 patients) received these drugs in the group of patients who did not received thiopurines (P < 0.001 and P < 0.001 respectively). Finally, 6.8% (29 patients) among those treated with thiopurines have received other immunosuppressants (Methotrexate, Tacrolimus, Cyclosporin), compare to 1% (4 patients) of patients not treated with thiopurines (P < 0.001). Among patients treated with thiopurines, 3.97% developed a malignancy, and among those not treated neoplasms presented in 8.1% (P = 0.013). The most frequent neoplasms were colorectal ones (12 cases in patients not treated with thiopurines but none in treated, P < 0.001) followed by non-melanoma skin cancer (8 patients in treated with thiopurines and 6 in not treated, P > 0.05).. In our experience, thiopurine therapy did not increase malignancies development in IBD patients, and was an effective and safe treatment for these diseases.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Inflammatory Agents; Azathioprine; Chi-Square Distribution; Child; Child, Preschool; Drug Therapy, Combination; Female; Gastrointestinal Agents; Hospitals, University; Humans; Incidence; Inflammatory Bowel Diseases; Logistic Models; Male; Mercaptopurine; Middle Aged; Multivariate Analysis; Neoplasms; Odds Ratio; Retrospective Studies; Risk Assessment; Risk Factors; Spain; Young Adult

Topics: Azathioprine; Crohn Disease; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Mercaptopurine; Neoplasms

The thiopurines, 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG), are used in the treatment of leukemia. Incorporation of deoxythioguanosine nucleotides (dG(s)) into the DNA of thiopurine-treated cells causes cell death, but there is also evidence that thiopurine metabolites, particularly the 6-MP metabolite methylthioinosine monophosphate (MeTIMP), inhibit de novo purine synthesis (DNPS). The toxicity of DNPS inhibitors is influenced by methylthioadenosine phosphorylase (MTAP), a gene frequently deleted in cancers. Because the growth of MTAP-deleted tumor cells is dependent on DNPS or hypoxanthine salvage, we would predict such cells to show differential sensitivity to 6-MP and 6-TG. To test this hypothesis, sensitivity to 6-MP and 6-TG was compared in relation to MTAP status using cytotoxicity assays in two MTAP-deficient cell lines transfected to express MTAP: the T-cell acute lymphoblastic leukemic cell line, Jurkat, transfected with MTAP cDNA under the control of a tetracycline-inducible promoter, and a lung cancer cell line (A549-MTAP(-)) transfected to express MTAP constitutively (A549-MTAP(+)). Sensitivity to 6-MP or methyl mercaptopurine riboside, which is converted intracellularly to MeTIMP, was markedly higher in both cell lines under MTAP(-) conditions. Measurement of thiopurine metabolites support the hypothesis that DNPS inhibition is a major cause of cell death with 6-MP, whereas dG(s) incorporation is the main cause of cytotoxicity with 6-TG. These data suggest that thiopurines, particularly 6-MP, may be more effective in patients with deleted MTAP.

Topics: Antimetabolites, Antineoplastic; Cell Line, Tumor; Drug Resistance, Neoplasm; Gene Deletion; Humans; Immunoblotting; Mercaptopurine; Neoplasms; Purine-Nucleoside Phosphorylase; Purines; Thioguanine; Thioinosine; Thionucleotides

The use of peptide receptors as targets for tumor-selective therapies was envisaged years ago with the findings that receptors for different endogenous regulatory peptides are overexpressed in several primary and metastatic human tumors, and can be used as tumor antigens. Branched peptides can retain or even increase, through multivalent binding, the biological activity of a peptide and are very resistant to proteolysis, thus having a markedly higher in vivo activity compared with the corresponding monomeric peptides. Oligo-branched peptides, containing the human regulatory peptide neurotensin (NT) sequence, have been used as tumor-specific targeting agents. These peptides are able to selectively and specifically deliver effector units, for cell imaging or killing, to tumor cells that overexpress NT receptors. Results obtained with branched NT conjugated to different functional units for tumor imaging and therapy indicate that branched peptides are promising novel multifunctional targeting molecules. This study is focused on the role of the releasing pattern of drug-conjugated branched NT peptides. We present results obtained with oligo-branched neurotensin peptides conjugated to 6-mercaptopurin (6-MP), combretastain A-4 (CA4) and monastrol (MON). Drugs were conjugated to oligo-branched neurotensin through different linkers, and the mode-of-release, together with cytotoxicity, was studied in different human cancer cell lines. The results show that branched peptides are very promising pharmacodelivery options. Among our drug-armed branched peptides, NT4-CA4 was identified as a candidate for further development and evaluation in preclinical pharmacokinetic and pharmacodynamic studies. This peptide-drug exhibits significant activity against pancreas and prostate human cancer cells. Consequently, this derivative is of considerable interest due to the high mortality rates of pancreas neuroendocrine tumors and the high incidence of prostate cancer.

Topics: Antineoplastic Agents; Drug Design; Drug Evaluation, Preclinical; Drug Screening Assays, Antitumor; Humans; Mercaptopurine; Neoplasms; Neurotensin; Peptides; Pyrimidines; Receptors, Neurotensin; Stilbenes; Thiones

Benefits of immunosuppressive therapy in Crohn's disease have been demonstrated in controlled trials; however, it is unclear whether these drugs alter the longer-term natural history of this condition.. To assess changes in disease outcomes in a population-based cohort of patients diagnosed in Cardiff from 1986 to 2003. Case notes from Crohn's disease incidence studies in Cardiff were reviewed retrospectively for disease characteristics and follow-up information on drug therapy, and the need for surgery for Crohn's disease. The study population was divided into three groups by year of diagnosis (Group A=1986-1991, Group B=1992-1997 and Group C=1998-2003).. 341 patients were included. Kaplan-Meier (KM) analysis showed increasing use of immunosuppressants over time. At 5 years after diagnosis this was 11% in Group A, 28% in Group B, and 45% in Group C (p=0.001) and the median time to start of thiopurines was 77, 21 and 11 months in Group A, B and C respectively. There was a significant reduction in long-term steroid use at 5 years post diagnosis: 45 (44%), 31 (31%) and 24 (19%) patients in Group A, B and C respectively (p=0.001). KM analysis showed a significant reduction in the cumulative probability of intestinal surgery: At 5 years this was 59% (Group A), 37% (Group B) and 25% (Group C) (p=0.001). In a multivariate Cox analysis, year of diagnosis, disease location, oral corticosteroids within 3 months of diagnosis and early thiopurine use (within the first year of diagnosis) were all independent factors affecting likelihood of intestinal surgery.. This population-based cohort shows marked changes in rates of surgery, and the reduction is independently associated with year of diagnosis, and associated temporally with increased and earlier thiopurine use.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Azathioprine; Child; Child, Preschool; Crohn Disease; Digestive System Surgical Procedures; Drug Administration Schedule; Epidemiologic Methods; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Middle Aged; Neoplasms; Wales; Young Adult

The aim of this study was to contrast protein binding of morphine and morphine-6 glucuronide in cord blood and children with adults and examine impact of chemotherapy and other factors. Morphine binding was measured in spiked samples from 18 adults and 18 neonates (cord blood), and compared with six children with cancer receiving morphine. The influence of the following was examined: Human serum albumin (HSA), alpha-1 acid glycoprotein (AAG), non-esterified fatty acids (NEFA); palmitic acid and oleic acid, pH, vincristine, methotrexate, 6-mercaptopurine and M6G. binding correlated with concentrations of albumin and alpha1 acid glycoprotein. In vitro, binding was not altered by vincristine, 6-mercaptopurine, methotrexate or M6G. Compared with HSA alone, AAG increased binding, palmitic acid reduced it and oleic acid had no effect. Binding was unaffected by pH in samples from patients. Morphine binding was influenced by concentrations of albumin, AAG and morphine itself, but not by age.

Topics: Adolescent; Adult; Age Factors; Analgesics, Opioid; Antineoplastic Agents; Blood Proteins; Child; Child, Preschool; Fatty Acids, Nonesterified; Female; Fetal Blood; Humans; Hydrogen-Ion Concentration; In Vitro Techniques; Infant, Newborn; Male; Mercaptopurine; Methotrexate; Middle Aged; Morphine; Morphine Derivatives; Neoplasms; Orosomucoid; Protein Binding; Serum Albumin; Vincristine

Studies to date have not confirmed an association between neoplasms and inflammatory bowel disease (IBD) treated with 6-mercaptopurine (6-MP). We have observed the occurrence of some neoplasms in IBD patients who developed sustained leukopenia as a result of treatment with 6-MP. As a result, we sought to compare the incidence of neoplasms in patients who developed sustained leukopenia after taking 6-MP compared with patients treated with 6-MP without sustained leukopenia.. A database containing the medical records of more than 600 patients treated with 6-MP for IBD at 1 center between 1965 and 2002 was searched. The patients were divided into 2 groups. The study group consisted of patients who developed sustained leukopenia, defined as a white blood cell count of less than 4000 for 20 or more days. The control group patients matched those in the study group for age and sex. There were 3 matched controls for each patient in the study group.. Eighteen patients developed sustained leukopenia and, of these, 4 developed neoplasms (22%)-2 leukemias, 1 non-Hodgkin's lymphoma, and 1 breast cancer. Of the 54 patients in the control group, 4 developed neoplasms (7%) (P = .10). Post hoc analysis revealed a statistically significant difference in the number of hematologic malignancies in the group with sustained leukopenia (P = .014). There was no significant difference between the 2 groups for all confounding variables examined.. There was a trend toward a greater number of total malignancies in the sustained leukopenic patients. The data suggest that it is those patients who develop sustained leukopenia while taking 6-MP/azathioprine who are most at risk.

Topics: Adult; Aged; Case-Control Studies; Databases as Topic; Female; Humans; Immunosuppressive Agents; Incidence; Inflammatory Bowel Diseases; Leukopenia; Male; Mercaptopurine; Middle Aged; Neoplasms; Retrospective Studies

To assess thiopurine S-methyltransferase (TPMT) phenotype and genotype in patients who were intolerant to treatment with mercaptopurine (MP) or azathioprine (AZA), and to evaluate their clinical management.. TPMT phenotype and thiopurine metabolism were assessed in all patients referred between 1994 and 1999 for evaluation of excessive toxicity while receiving MP or AZA. TPMT activity was measured by radiochemical analysis, TPMT genotype was determined by mutation-specific polymerase chain reaction restriction fragment length polymorphism analyses for the TPMT*2, *3A, *3B, and *3C alleles, and thiopurine metabolites were measured by high-performance liquid chromatography.. Of 23 patients evaluated, six had TPMT deficiency (activity < 5 U/mL of packed RBCs [pRBCs]; homozygous mutant), nine had intermediate TPMT activity (5 to 13 U/mL of pRBCs; heterozygotes), and eight had high TPMT activity (> 13.5 U/mL of pRBCs; homozygous wildtype). The 65.2% frequency of TPMT-deficient and heterozygous individuals among these toxic patients is significantly greater than the expected 10% frequency in the general population (P <.001, chi(2)). TPMT phenotype and genotype were concordant in all TPMT-deficient and all homozygous-wildtype patients, whereas five patients with heterozygous phenotypes did not have a TPMT mutation detected. Before thiopurine dosage adjustments, TPMT-deficient patients experienced more frequent hospitalization, more platelet transfusions, and more missed doses of chemotherapy. Hematologic toxicity occurred in more than 90% of patients, whereas hepatotoxicity occurred in six patients (26%). Both patients who presented with only hepatic toxicity had a homozygous-wildtype TPMT phenotype. After adjustment of thiopurine dosages, the TPMT-deficient and heterozygous patients tolerated therapy without acute toxicity.. There is a significant (> six-fold) overrepresentation of TPMT deficiency or heterozygosity among patients developing dose-limiting hematopoietic toxicity from therapy containing thiopurines. However, with appropriate dosage adjustments, TPMT-deficient and heterozygous patients can be treated with thiopurines, without acute dose-limiting toxicity.

Topics: Adolescent; Adult; Antimetabolites, Antineoplastic; Azathioprine; Child; Child, Preschool; Female; Genotype; Hospitalization; Humans; Infant; Male; Mercaptopurine; Methyltransferases; Neoplasms; Phenotype; Platelet Transfusion; Polymorphism, Restriction Fragment Length; Risk Factors; Thrombocytopenia

In vitro growth inhibition assays were performed using human cancer cell lines at various concentrations with experimental anticancer drugs such as the cryptophycins and other cytotoxins. The effect of variations in assay parameters on the observed growth inhibition of these anticancer therapeutic agents was determined. The results demonstrated that the observed inhibitory activity of these compounds varied inversely with the cell concentrations used. The observed differences in activity between different cytotoxins were not necessarily proportionate. Thus, the relative activities of two toxins also varied with cell concentration. Furthermore, the sensitivity of these cell lines to the cytostatic purine analog, 6-mercaptopurine (used as a control), varied with cell concentration as well. The activity of this compound was dependent on the medium used for cell growth, yielding good activity in Eagle's minimum essential medium, but not in Ham's F-12 (Kaigin) medium. Moreover, growth inhibition by cryptophycin as well as 6-mercaptopurine was also dependent on the serum concentration in the medium. Finally, the sensitivity of the cancer cell lines to various organic solvents commonly used as drug vehicles for in vitro testing, such as ethanol, dimethylformamide, and dimethylsulfoxide, was likewise found to vary inversely with cell concentration.

Topics: Antineoplastic Agents; Cell Division; Culture Media; Depsipeptides; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Inhibitory Concentration 50; Mercaptopurine; Neoplasms; Peptides, Cyclic; Solvents; Tumor Cells, Cultured

Most complications of 6-mercaptopurine (6MP) used in the treatment of inflammatory bowel disease (IBD) occur early, whereas neoplasms occur late in the course. Concern persists that the risk is increased when 6MP is used. We report our experience with malignant tumors developing over 27 yr of treating IBD patients with 6MP.. A total of 591 patients with IBD treated with 6MP between 1969 and 1997 were followed or traced until present to identify all malignant tumors and blood dyscrasias that had developed to determine the type, distribution, and duration of the IBD, the dose and duration of 6MP therapy, the concurrent versus previous use of 6MP, the incidence and probable relationship of 6MP to specific neoplasms, and whether the 6MP had been effective in treatment.. A total of 550 patients (93%) fulfilled the criteria for follow-up; these included 380 with Crohn's disease (CD) and 170 with ulcerative colitis (UC). Twenty-five patients had developed neoplasms (16 of 380 CD and nine of 170 UC) (p = 0.66). In half of the cases, the goal of therapy had been achieved with 6MP. In 10 patients, the neoplasm was diagnosed while the patients were taking 6MP (40%) and in 15, many years after the 6MP had been terminated (60%). The incidence of neoplasms (25 of 550) was 2.7/1000 patient-years of follow-up. The most common neoplasms were found in the bowel (eight of 550, 1.6%; five CD, and three UC), and breast (three, 0.5%; two CD, and one UC). Non-Hodgkins lymphomas occurred in two patients with CD; one was cerebral and the other abdominal. One patient with CD developed leukemia. The duration of 6MP therapy ranged from 5 months to 22 yr, with a mean of 5 yr. The dose of 6MP ranged from a quarter of a tablet/day (12.5 mg) to 100 mg/day, with the majority in a range from 50 to 75 mg/day.. In no instance could a neoplasm be attributed to the use of 6MP. The incidence of colon cancer is not greater than that with long standing colitis. Suspicion of a relationship between 6MP and leukemia/lymphoma persists, but the incidence is low. This must be weighed against the improved quality of life due to 6MP for patients with IBD.

Topics: Abdominal Neoplasms; Adult; Aged; Aged, 80 and over; Brain Neoplasms; Breast Neoplasms; Colitis, Ulcerative; Crohn Disease; Drug Administration Schedule; Female; Follow-Up Studies; Hematologic Diseases; Humans; Immunosuppressive Agents; Incidence; Inflammatory Bowel Diseases; Intestinal Neoplasms; Leukemia; Lymphoma, Non-Hodgkin; Male; Mercaptopurine; Middle Aged; Neoplasms; Risk Factors; Time Factors

Several factors can limit the use of therapeutic drug monitoring (TDM) for cancer chemotherapeutic agents, including poorly defined concentration-effect relationships for many antineoplastic agents. This is further complicated by cancer being a highly heterogeneous group of diseases, each of which may have a unique concentration-effect relationship for any given drug or drug combination. Nonetheless, TDM clearly has the potential to improve the clinical use of antineoplastic agents, most of which have very narrow therapeutic indices and highly variable pharmacokinetics. A substantial body of literature accumulating during the past 15 years demonstrates relationships between systemic exposure to various anticancer drugs and their toxic or therapeutic effects. This review highlights selected studies that illustrate concentration-effect relationship for the antineoplastic effects of 5-fluorouracil, mercaptopurine, and methotrexate. A much larger number of pharmacodynamic studies have established the relationship between serum concentration and dose-limiting toxicities for anticancer agents, including epipodophyllotoxins, platinum compounds, camptothecin, anthracyclines, and antimetabolites. In this review we will focus on anticancer drugs for which the pharmacodynamics of antineoplastic effects have been elucidated. We will also address issues critical to the optimal use of TDM in a clinical setting, which requires effective participation by a multidisciplinary team of professionals.

Topics: Antineoplastic Agents; Dose-Response Relationship, Drug; Drug Monitoring; Fluorouracil; Humans; Mercaptopurine; Methotrexate; Neoplasms; Outcome Assessment, Health Care

We evaluated clinical characteristics and growth in 51 (24 males) long-term survivors of childhood cancer (median follow up 12.7 years). Patients were shorter, had a higher proportion of body fat and higher systolic blood pressure than their controls. The change in relative height during treatment was -0.83 standard deviation score (S.D.S.) in patients with cranial irradiation and -0.32 S.D.S. in patients without cranial irradiation; the figures after treatment were -0.56 and 0.20 S.D.S., respectively. Half (r2 = 0.50) of the variation in growth retardation during therapy could be explained by the cumulative doses of 6-mercaptopurine (6-MP) and vincristine and relative height at diagnosis. Cranial irradiation, increased relative height at diagnosis and young age at diagnosis were significant predictors of growth failure over the total observation period, explaining 43% of the variation. We conclude that long-term survivors of childhood cancer have impaired linear growth, increased body fat mass and elevated systolic blood pressure. Young children who are tall for their age at diagnosis and treated with cranial irradiation have the highest risk of impaired growth after the diagnosis. High doses of 6-MP seem to contribute significantly to growth retardation during therapy.

Topics: Adolescent; Adult; Antimetabolites, Antineoplastic; Antineoplastic Agents; Body Mass Index; Child; Child, Preschool; Cranial Irradiation; Female; Follow-Up Studies; Growth; Growth Disorders; Humans; Infant; Linear Models; Male; Matched-Pair Analysis; Mercaptopurine; Neoplasms; Risk Factors; Survivors

Topics: Aged; Aged, 80 and over; Azathioprine; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Neoplasms; Risk Factors

Topics: Adolescent; Crohn Disease; Humans; Mercaptopurine; Neoplasms

A phase II pediatric trial of a continuous intravenous infusion of 6-mercaptopurine (6-MP) in patients with refractory solid tumors or lymphoma was performed. The dosing schedule of 50 mg/m2 per hour for 48 h was chosen to produce optimal cytotoxic concentrations of 6-MP. There were no complete or partial responses in the 40 patients entered in the trial. Accrual was sufficient for the conclusion to be drawn that there was greater than 95% probability that the true response rate was no greater than 22% and 26% in osteosarcoma and Ewing's sarcoma, respectively. Dose-limiting toxicity was observed in one-third of the patients and included reversible hepatotoxicity, myelosuppression, and mucositis. The excellent penetration of drug into the cerebrospinal fluid (CSF) suggests that future trials of this intravenous dosing schedule should be conducted on tumors of the CNS.

Topics: Adolescent; Adult; Agranulocytosis; Child; Child, Preschool; Drug Evaluation; Humans; Infant; Infusions, Intravenous; Liver; Mercaptopurine; Neoplasms; Thrombocytopenia

We assess toxicity related to 6-mercaptopurine in the treatment of inflammatory bowel disease by reporting our experience with 396 patients (120 patients with ulcerative colitis, 276 with Crohn disease) observed over 18 years. Follow-up data for a mean period of 60.3 months were obtained for 90% of the patients. Toxicity directly induced by 6-mercaptopurine included pancreatitis in 13 patients (3.3%), bone marrow depression in 8 (2%), allergic reactions in 8 (2%), and drug hepatitis in 1 (0.3%). These complications were reversible in all cases with no mortality. Most cases of marrow depression occurred earlier in our experience, when the initial drug doses used were higher. Infectious complications were seen in 29 patients (7.4%), of which 7 (1.8%) were severe, including one instance of herpes zoster encephalitis. All infections were reversible with no deaths. Twelve neoplasms (3.1%) were observed, but only 1 (0.3%), a diffuse histiocytic lymphoma of the brain, had a probable association with the use of 6-mercaptopurine. Our data, showing a low incidence of toxicity in 396 patients, coupled with the previously demonstrated efficacy of 6-mercaptopurine in the treatment of inflammatory bowel disease, indicate that the drug is a reasonable alternative in the management of patients with intractable inflammatory bowel disease.

Topics: Adolescent; Adult; Aged; Bone Marrow Diseases; Chemical and Drug Induced Liver Injury; Child; Colitis, Ulcerative; Crohn Disease; Double-Blind Method; Drug Hypersensitivity; Female; Follow-Up Studies; Humans; Infections; Male; Mercaptopurine; Middle Aged; Neoplasms; Pancreatitis; Pregnancy; Time Factors

The accumulation, metabolism, and retention of mercaptopurine (MP) was studied in four human neoplastic cell lines (three acute leukemia lines Molt-4, CCRF-CEM, and HL-60; and one Burkitt's lymphoma line, Wilson), each of which was sensitive to MP. Two cell lines resistant to MP (WilsonR and CCRF-CEMR) were also studied. The cell lines were incubated for 3 h in 10 microM [14C]MP and then placed in drug-free media for an additional 3 h. Cell samples were obtained at regular intervals, and the intracellular MP metabolites were measured in the acid-soluble fractions by anion-exchange high-pressure liquid chromatography. MP accumulated progressively within cells during the 3-h drug exposure period and declined rapidly when the cells were placed in drug-free media. Over 80% of the intracellular MP was present in the form of three nucleotide metabolites, MP ribose monophosphate, thioxanthosine monophosphate, and thioguanosine monophosphate. MP ribose monophosphate was found in greatest amount, accounting for 59-85% of the intracellular metabolite pool. Thioxanthosine monophosphate thioguanosine monophosphate were detected in lesser amounts. Study of leukemic cells obtained from patients demonstrated a similar pattern of MP accumulation, metabolism, and retention, although the overall amounts of the various metabolites formed were less. In contrast, there was essentially no MP nucleotide metabolite formation in the two MP-resistant cell lines. A more complete understanding of the cellular pharmacokinetics of MP in human neoplastic cells is likely to lead to a more rational use of the drug in the clinical setting.

Topics: Adenosine Triphosphate; Cell Line; Chromatography, High Pressure Liquid; Guanosine Triphosphate; Humans; Kinetics; Leukemia; Mercaptopurine; Neoplasms; Nucleotides; Phosphoribosyl Pyrophosphate

The use of drugs in combination for the management of cancer patients aims at the increased therapeutic advantage by elimination the problem of the heterogeneous sensitivity of cancer cells to anticancer drugs, and by delaying or preventing the development of drug resistance within given tumors. Theoretically, the effects of drugs in combination are classified as antagonistic, subadditive, additive and synergistic. Since these results hold for both tumors and hosts, the effects of combined drugs should be considered in terms of therapeutic index. From this viewpoint, the choice and administration schedule of drugs in combination must be synergistic or additive for the tumors and antagonistic or subadditive for the hosts in regard to combined effects. Thus, the rationale for combined drug therapy should be considered from the aspects of biochemical basis, drug resistance, cytokinetic and pharmacologic rationales, and toxicologic basis.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Doxorubicin; Drug Administration Schedule; Drug Synergism; Fluorouracil; Humans; Mercaptopurine; Methotrexate; Neoplasms; Nimustine; Nitrosourea Compounds

Topics: Allopurinol; Animals; Humans; Immunosuppressive Agents; Kidney Transplantation; Mercaptopurine; Neoplasms; Xanthine Oxidase

The bioavailability of oral mercaptopurine (MP) is poor, and plasma levels following p.o. dosing are highly variable. In an attempt to circumvent these problems, we conducted a Phase I trial and clinical pharmacological study of MP administered as a prolonged i.v. infusion. An infusion rate of 50 mg/sq m/h, which was designed to achieve therapeutic drug levels in plasma, was used in all patients. The infusion duration was escalated in 12-h increments. Thirty-eight patients were evaluated. The dose-limiting toxicity was mucositis. Other reversible toxicities were myelosuppression and hepatotoxicity. An infusion duration of 48 h was found to be safe, unassociated with dose-limiting toxicity. Objective responses were seen in five patients. The mean plasma steady-state MP concentration achieved was 6.9 microM with little interpatient variability seen. Allopurinol coadministration had no effect on the plasma pharmacokinetics of i.v. MP. However, allopurinol did alter the urinary metabolite pattern, decreasing thiouric acid and increasing MP and thioxanthine levels. The steady-state cerebrospinal fluid:plasma ratio for MP was 0.27, suggesting that this approach may be of value in the treatment of central nervous system cancer. MP can be safely administered as a 48-h i.v. infusion at a dose rate which reliably achieves MP levels associated with optimal antileukemic activity in vitro.

Topics: Drug Evaluation; Humans; Infusions, Parenteral; Kinetics; Mercaptopurine; Neoplasms

Topics: Adolescent; Body Height; Child; Child Development; Child, Preschool; Female; Follow-Up Studies; Humans; Infant; Infant, Newborn; Mercaptopurine; Methotrexate; Neoplasms; Pregnancy; Pregnancy Complications

The risks of embryonic, fetal, gondal damage of cancer chemotherapy are reviewed. Contrasting with the numerous malformations seen in laboratory animals, the teratogenic risk is low in man. Methotrexate is really dangerous during the first trimester of pregnancy. In malignant haematological diseases and solid tumours, the prognosis of the disease is the essential target but the use of immuno-suppressive drugs in non-malignant diseases is hazardous before 40 years of age. All the investigations show that alkylating agents injure the gonads. Young women should be avised to use contraceptives. The future of children born after administration of anti cancer drugs is uncertain. Sterility, carcinogenic risk, mutation, teratogenetic effects in future generations cannot be ruled out.

Topics: Abnormalities, Drug-Induced; Abortion, Spontaneous; Adult; Alkaloids; Animals; Antibiotics, Antineoplastic; Antineoplastic Agents; Busulfan; Chlorambucil; Cyclophosphamide; Embryo, Mammalian; Female; Fetus; Folic Acid Antagonists; Humans; Infertility; Male; Mercaptopurine; Mice; Neoplasms; Pregnancy; Pregnancy Complications; Rabbits; Rats

The binding of N-[-5-(6-purinylthio)-valeryl]-glycin ethylester (butocin, PVG) to serum proteins and pure human albumin was studied using the method of equilibrium dialysis. Its binding to protein in sera diluted 1:1 of 10 patients with malignant disease averaged 48.4 +/- 7.07%. At the butocin concentration of 20 micrograms/ml an average of 36% of butocin were bound to pure albumin. Only a small portion was bound to globulin fractions. Measurements of the saturation curve showed butocin to be bound to albumin molecule by one binding centre with a microscopic association constant kappa = 1.7 . 10(3) mol/l.

Topics: Blood Proteins; Humans; In Vitro Techniques; Mercaptopurine; Neoplasms; Protein Binding; Serum Albumin; Serum Globulins

Topics: Allopurinol; Anaphylaxis; Anemia; Antibiotics, Antineoplastic; Bicarbonates; Blood Transfusion; Child; Child, Preschool; Cystitis; Disseminated Intravascular Coagulation; Erythrocytes; Female; Furosemide; Heart Arrest; Heparin; Humans; Hydrogen-Ion Concentration; Kidney; Leukemia; Lung Diseases; Male; Mercaptopurine; Mutation; Neoplasms; Phospholipids; Renal Dialysis; Thrombocytopenia; Uric Acid

The pharmacokinetics of Butocine (glycine, N-[1-oxo-5-(1H-purin-6-ylthio)pentyl], ethyl ester) was studied in 8 individuals with malignant tumor after a single oral dose of 500 mg. Butocine is quickly absorbed from the alimentary tract. Highest serum levels were found 45 minutes after administration. Its urinary excretion is very low (2.5 per cent in 15 hours), 1.7 per cent being eliminated 3 hours after administration. Its renal clearance is likwise very low, i.e. 1.5 ml/min compared with endogenous creatinine clearance of 81.2 ml/min.

Topics: Aged; Female; Humans; Kinetics; Male; Mercaptopurine; Middle Aged; Neoplasms

Topics: Adolescent; Adult; Aged; Female; Humans; Male; Mercaptopurine; Middle Aged; Neoplasms; Remission, Spontaneous

Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Agents; Carmustine; Cyclophosphamide; Drug Administration Schedule; Fluorouracil; Humans; Leukemia L1210; Lomustine; Mercaptopurine; Methotrexate; Mice; Neoplasms

Topics: Adrenal Cortex Hormones; Animals; Antineoplastic Agents; Chloramphenicol; Cyclophosphamide; Drug Interactions; Drug Therapy, Combination; Fluorouracil; Humans; Mercaptopurine; Methotrexate; Mice; Neoplasms; Prednisolone; Rats; Thioguanine; Vinca Alkaloids

Topics: Asparaginase; Child; Cyclophosphamide; Cytosine; Daunorubicin; Doxorubicin; Drug Therapy, Combination; Hodgkin Disease; Humans; Infant; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Lymphoma; Melphalan; Mercaptopurine; Methotrexate; Neoplasms; Nitrogen Mustard Compounds; Osteosarcoma; Prednisone; Procarbazine; Prognosis; Remission, Spontaneous; Rhabdomyosarcoma; Teniposide; Thioguanine; Vincristine; Wilms Tumor

Topics: Abnormalities, Drug-Induced; Azathioprine; Cortisone; Cyclophosphamide; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Infections; Infertility; Male; Mercaptopurine; Methotrexate; Neoplasms; T-Lymphocytes

A multiple drug regimen was given to 36 patients with advanced carcinomas of the head and neck. In 19 of the 24 patients who were assessable the tumour regressed more than 50%; in one it regressed by 25%; and in four it did not respond at all. Multiple drug chemotherapy should be given much earlier in the course of these cancers, preferably as an adjuvant to surgery or radiotherapy.

Topics: Antineoplastic Agents; Bleomycin; Doxorubicin; Drug Synergism; Drug Therapy, Combination; Ear Neoplasms; Fluorouracil; Head; Head and Neck Neoplasms; Humans; Hydroxyurea; Laryngeal Neoplasms; Maxillary Neoplasms; Mercaptopurine; Methotrexate; Mouth Neoplasms; Nasopharyngeal Neoplasms; Neoplasms; Tongue Neoplasms; Tonsillar Neoplasms; Vincristine

Topics: Animals; Carcinoma 256, Walker; Cyclophosphamide; Kinetics; Liver; Male; Mercaptopurine; Neoplasm Transplantation; Neoplasms; Perfusion; Rats; Transplantation, Homologous

Infections in the immunosuppressed cancer patient are caused by a wide variety of bacteria, viruses, fungi, and protozoa; many of these in the normal individual are saprophytes but will cause disease in the immunosuppressed patient, often with treatment failure. Patterns of infection are recognized, and this should enable the physician to plan a meaningful course of action when infection occurs in the compromised host. Obviously, it would be much better to prevent rather than have to treat infection in these immunosuppressed patients. Ideally, in the future, it is hoped that drugs which have less suppressive effect on defense mechanisms will provide a partial solution to the problem of infection in the immunosuppressed patient.

Topics: Adrenal Cortex Hormones; Alkylating Agents; Antineoplastic Agents; Azathioprine; Bacteria; Bacterial Infections; Folic Acid Antagonists; Humans; Immunity, Cellular; Immunosuppression Therapy; Immunosuppressive Agents; Infections; Lymphocytes; Mercaptopurine; Mycoses; Neoplasms; Phagocytosis; Protozoan Infections; Virus Diseases

Drug screening trials and general treatment of solid tumours in advanced cancer patients have been concerned only with the site of primary origin, regardless of where metastases might have seeded. Since the environment for tumour growth can differ appreciably at various anatomical sites, an investigation was undertaken to determine the effect of metastatic site on response to chemotherapy. Data from 1961 to 1965 of the screening trials of the Eastern Clinical Drug Evaluation Program were utilized. Response and location data extensive enough for analysis represented 6 sites of primary origin and 6 metastatic site groups, totalling 1687 lesions. Analysis of percentage reduction in tumour size after chemotherapy regimens of up to 60 days revealed a significant amount of variation associated with metastatic sites and a non-significant amount associated with sites of primary origin. Advanced primary tumours showed marked variation in responsiveness and some showed a difference in response to different drug groups. Generally, metastases responded better than the advanced primaries from which they were derived, except for those from breast tumours.

Topics: Antineoplastic Agents; Breast Neoplasms; Chlorambucil; Female; Fluorouracil; Genital Neoplasms, Female; Head and Neck Neoplasms; Humans; Lung Neoplasms; Melanoma; Mercaptopurine; Mitomycins; Neoplasm Metastasis; Neoplasms

Topics: Antineoplastic Agents; Busulfan; Chlorambucil; Cyclophosphamide; Cytarabine; Daunorubicin; Education, Medical, Continuing; Fluorouracil; Humans; Melphalan; Mercaptopurine; Methotrexate; Neoplasms; Procarbazine; Triaziquone; Vinblastine; Vincristine

Topics: Animals; Benzyl Compounds; Brain; DDT; Electron Spin Resonance Spectroscopy; Free Radicals; Humans; Kinetics; Leukemia; Liver; Lung Neoplasms; Lymphocytes; Mathematics; Melphalan; Mercaptopurine; Mice; Neoplasm Metastasis; Neoplasms; Neoplasms, Experimental; Nitrosourea Compounds; Rats; Thiotepa; Time Factors

Topics: Alkaloids; Alkylating Agents; Antibiotics, Antineoplastic; Antineoplastic Agents; Binding Sites; Cytarabine; Drug Synergism; Enzyme Therapy; Folic Acid Antagonists; Humans; Hydroxyurea; Leucovorin; Mechlorethamine; Mercaptopurine; Methotrexate; Mitomycins; Neoplasms; Nucleic Acids; Purines; Pyrimidines; Steroids; Thioguanine; Vinblastine; Vincristine

Topics: Administration, Oral; Blood Cell Count; Blood Platelets; Bone Marrow; Chlorambucil; Cyclophosphamide; Drug Therapy, Combination; Female; Hemoglobinometry; Humans; Leukocyte Count; Mechlorethamine; Mercaptopurine; Neoplasms; Oxymetholone; Prednisolone; Prognosis; Time Factors; Vinblastine; Vincristine

Topics: Adenine; Adenine Nucleotides; Animals; Carbon Isotopes; Carcinoma, Ehrlich Tumor; Erythrocytes; Guanine; Humans; Hypoxanthines; Mercaptopurine; Neoplasms; Nucleosides; Nucleotides; Pentosyltransferases; Phosphotransferases; Purines; Pyrimidines; Thioguanine

Topics: Adenine Nucleotides; Adult; Animals; Antibiotics, Antineoplastic; Arabinose; Carcinoma, Squamous Cell; Cricetinae; Dogs; Humans; Hypoxanthines; Kidney; Leukemia, Lymphoid; Lung Neoplasms; Lymphoma, Non-Hodgkin; Male; Mercaptopurine; Mice; Middle Aged; Neoplasms; Nucleosides; Nucleotidases; Nucleotides; Phosphorus; Rabbits; Sulfur Isotopes; Time Factors; Tritium

Topics: Adenine; Alkylating Agents; Analgesics; Anemia; Anti-Bacterial Agents; Antiemetics; Antimetabolites; Antineoplastic Agents; Drug Therapy; Expectorants; Folic Acid; Humans; Mercaptopurine; Methotrexate; Neoplasms; Pharmaceutical Preparations; Radiotherapy; Steroids; Tranquilizing Agents; Vitamins

Topics: Antineoplastic Agents; Azathioprine; Chlorambucil; Cyclophosphamide; Hair; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Melphalan; Mercaptopurine; Methotrexate; Neoplasms; Scleroderma, Systemic; Skin Diseases; Vinblastine

Topics: Amidohydrolases; Animals; Antineoplastic Agents; Drug Resistance; Humans; Mercaptopurine; Mice; Neoplasms; Neoplasms, Experimental; Nucleosides; Nucleotides; Oxidoreductases; Phosphotransferases; Prognosis; Purines

Topics: Adolescent; Adult; Antineoplastic Agents; Child; Child, Preschool; Chromatin; Cyclophosphamide; Daunorubicin; Female; Humans; Male; Mercaptopurine; Methotrexate; Mouth Mucosa; Neoplasms; Prednisone; Procarbazine; Vincristine

Topics: Adult; Aged; Antineoplastic Agents; Chlorambucil; Cyclophosphamide; Female; Humans; Male; Mercaptopurine; Methotrexate; Middle Aged; Neoplasms; Vincristine

Topics: Adult; Bilirubin; Blood Group Incompatibility; Blood Proteins; Female; Fetus; gamma-Globulins; Humans; Immunoglobulins; Immunosuppressive Agents; Infant, Newborn; Infant, Premature; Mercaptopurine; Methotrexate; Neoplasms; Pregnancy; Pregnancy Complications; Rh-Hr Blood-Group System; Umbilical Cord

Topics: Adrenal Cortex Hormones; Animals; Antibodies; Antibody Formation; Antilymphocyte Serum; Antineoplastic Agents; Azathioprine; Cyclophosphamide; Humans; Hypersensitivity, Delayed; Immunity, Cellular; Immunoglobulins; Immunosuppressive Agents; Kidney Transplantation; Mercaptopurine; Methotrexate; Neoplasms; Skin Transplantation; Transplantation Immunology

Topics: Adolescent; Adult; Aged; Asparaginase; Azaserine; Burkitt Lymphoma; Central Nervous System Diseases; Chemical and Drug Induced Liver Injury; Child; Drug Hypersensitivity; Escherichia coli; Female; Humans; Leukemia, Lymphoid; Leukopenia; Lymphoma, Non-Hodgkin; Lymphopenia; Male; Mercaptopurine; Methotrexate; Middle Aged; Neoplasms; Pancreatitis; Thrombocytopenia

Topics: Breast Neoplasms; Cobalt Isotopes; Cyclophosphamide; Dactinomycin; DNA, Neoplasm; Female; Humans; Male; Mercaptopurine; Methotrexate; Neoplasm Metastasis; Neoplasms; Prednisone; Radiotherapy Dosage; RNA, Messenger; Testicular Neoplasms

Topics: Antimetabolites; Blood Cells; Cell Line; Culture Techniques; Cytarabine; Fluorouracil; Humans; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Mercaptopurine; Methotrexate; Mitosis; Neoplasms

Topics: Antineoplastic Agents; Breast Neoplasms; Colonic Neoplasms; Cytarabine; Female; Fluorouracil; Humans; Lung Neoplasms; Mercaptopurine; Methotrexate; Neoplasms; Prognosis; Time Factors

Topics: Adenocarcinoma; Antineoplastic Agents; Chlorambucil; Colchicine; Culture Techniques; Cyclophosphamide; Dactinomycin; Female; Floxuridine; Fluorouracil; Hodgkin Disease; Humans; Melphalan; Mercaptopurine; Methotrexate; Nandrolone; Neoplasms; Nitrogen Mustard Compounds; Norethindrone; Prednisolone; Progesterone; Testosterone; Thiotepa; Uterine Neoplasms; Vinblastine

Topics: Antineoplastic Agents; Culture Techniques; Humans; Mercaptopurine; Methods; Neoplasms; Nucleotides; Ribose; Spectrum Analysis; Ultraviolet Rays

Topics: Adolescent; Adult; Animals; Antineoplastic Agents; Chemical and Drug Induced Liver Injury; Chlorambucil; Cyclophosphamide; Female; Humans; Liver Function Tests; Male; Mechlorethamine; Mercaptopurine; Methotrexate; Middle Aged; Mitomycins; Neoplasms; Rats; Urethane; Vinblastine; Vincristine

Topics: Anemia, Hemolytic; Culture Techniques; Cyclophosphamide; Cytarabine; Humans; Immune Tolerance; Lectins; Leukemia; Lymphocytes; Mercaptopurine; Methotrexate; Neoplasms; Prednisolone; Smallpox Vaccine; Uveitis; Vincristine

Topics: Animals; Carcinoma, Ehrlich Tumor; Female; Mercaptopurine; Mice; Neoplasm Transplantation; Neoplasms; Sarcoma 180; Thiosemicarbazones; Vitamin B 6 Deficiency

Topics: Adult; Aged; Blood Cell Count; Blood Platelets; Cell Nucleus; Female; Humans; Male; Mercaptopurine; Methotrexate; Microscopy; Middle Aged; Neoplasms

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Adenocarcinoma, Scirrhous; Antibiotics, Antineoplastic; Antineoplastic Agents; Breast Neoplasms; Carcinoma, Squamous Cell; Culture Techniques; Flavonoids; Fluorouracil; HeLa Cells; Humans; Lung Neoplasms; Melphalan; Mercaptopurine; Methods; Mitomycins; Neoplasms; Rectal Neoplasms; Stomach Neoplasms

Topics: Adenine; Animals; Carcinoma, Hepatocellular; Guanine; Liver Neoplasms; Mercaptopurine; Neoplasms; Neoplasms, Experimental; Oxides; Rats; Xanthines

Topics: Androgens; Anti-Bacterial Agents; Antineoplastic Agents; Busulfan; Chlorambucil; Cyclophosphamide; Estrogens; Glucocorticoids; Humans; Leukemia; Mercaptopurine; Neoplasms; Plant Extracts; Plants; Triaziquone; Triethylenemelamine; Vincristine

Topics: Animals; Anti-Bacterial Agents; Antineoplastic Agents; Cyclophosphamide; Estrogens; Humans; Mercaptopurine; Methotrexate; Mice; Neoplasm Transplantation; Neoplasms; Neoplasms, Experimental; Nitrogen Mustard Compounds

Topics: Animals; Antineoplastic Agents; Cyclophosphamide; Dactinomycin; Hyperbaric Oxygenation; Mechlorethamine; Mercaptopurine; Methotrexate; Mice; Mitomycins; Neoplasms; Nitrogen Mustard Compounds; Rats; Thiotepa

Topics: Antimetabolites; Humans; Inflammation; Leukemia; Mercaptopurine; Methotrexate; Neoplasms; Uveitis

Topics: Antineoplastic Agents; Fluorouracil; Humans; Mercaptopurine; Models, Theoretical; Neoplasms; Statistics as Topic

Topics: Alkylating Agents; Carbamates; Chlorambucil; Fluorouracil; Humans; Leukocyte Count; Mercaptopurine; Mitomycins; Neoplasms; Statistics as Topic

Topics: Alkylating Agents; Carbamates; Chlorambucil; Fluorouracil; Humans; Leukocyte Count; Leukopenia; Mercaptopurine; Mitomycins; Neoplasms; Thrombocytopenia

Topics: Adrenal Cortex Hormones; Alkylating Agents; Child; Cyclophosphamide; Drug Therapy; Herpes Zoster; Hodgkin Disease; Leukemia; Lymphoma; Mechlorethamine; Mercaptopurine; Methotrexate; Neoplasms; Prednisolone; Surgical Procedures, Operative; Thrombocytopenia

Topics: Antineoplastic Agents; Child; Chlorambucil; Cyclophosphamide; Drug Therapy; Ganglioneuroma; Gastrointestinal Diseases; Hodgkin Disease; Leukemia; Leukemia, Myeloid; Liver Neoplasms; Lymphoma; Mechlorethamine; Mercaptopurine; Methotrexate; Neoplasms; Pathology; Radiation Injuries; Stomach; Toxicology; Vinblastine; Vincristine; Wilms Tumor

Topics: Adenine; Animals; Antimetabolites; Guanine; Mercaptopurine; Metabolism; Mice; Neoplasms; Neoplasms, Experimental; Nucleosides; Purine Nucleosides; Purines; Research

Topics: Antineoplastic Agents; Central Nervous System Diseases; Child; Clinical Laboratory Techniques; Drug Therapy; Headache; Humans; Intracranial Pressure; Leukemia; Mercaptopurine; Methotrexate; Neoplasms; Papilledema; Prednisone; Vomiting

Topics: Adolescent; Adrenal Cortex Hormones; Deafness; Drug Therapy; Leukemia; Leukemia, Lymphoid; Mercaptopurine; Neoplasms; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Topics: Bone Marrow Examination; Drug Therapy; Eosinophilic Granuloma; Lymphoma; Mechlorethamine; Mercaptopurine; Neoplasms; Pathology; Prednisone

Topics: Animals; Breast Neoplasms; Carcinogens; Cyclophosphamide; Dactinomycin; Diet; Diet Therapy; Humans; Mammary Neoplasms, Animal; Mammary Neoplasms, Experimental; Mechlorethamine; Mercaptopurine; Methotrexate; Methylcholanthrene; Neoplasms; Rats; Research; Toxicology

Topics: Biomedical Research; Biometry; Blood Cell Count; Leukemia; Leukemia, Lymphoid; Lymphocytes; Mathematics; Mercaptopurine; Methotrexate; Neoplasms; Therapeutics

Topics: Alkylating Agents; Aminopterin; Busulfan; Hodgkin Disease; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Lymphoma; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Mechlorethamine; Mercaptopurine; Methotrexate; Multiple Myeloma; Neoplasms; Pathology; Primary Myelofibrosis; Sarcoma; Triethylenemelamine; Tuberculosis; Tuberculosis, Pulmonary; Urethane

Topics: Child; Drug Therapy; Leukemia; Mercaptopurine; Methotrexate; Neoplasms; Remission Induction

Topics: Adenine Nucleotides; Animals; Liver; Mercaptopurine; Metabolism; Mice; Neoplasms; Neoplasms, Experimental; Nucleotides; Pharmacology; Research; Sarcoma 180

Topics: Animals; Estradiol; Friends; Leukemia; Leukemia Virus, Murine; Leukemia, Experimental; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Mercaptopurine; Methylcellulose; Mice; Mitomycin; Mitomycins; Neoplasm Transplantation; Neoplasms; Pharmacology; Research; Sarcoma; Triethylenemelamine; Urethane

Topics: Acute Disease; Adolescent; Aminopterin; Child; Humans; Leukemia; Mercaptopurine; Neoplasms; Prednisone; Thymectomy

Topics: Acute Disease; Adrenal Cortex Hormones; Androgens; Cyclophosphamide; Humans; Leukemia; Mercaptopurine; Methotrexate; Neoplasms; Prednisone; Vincristine

Topics: Adolescent; Bone Marrow; Bone Marrow Examination; Child; Humans; Intestines; Kidney; Leukemia; Liver; Lung; Male; Mercaptopurine; Methotrexate; Neoplasms; Pathology; Testis

Topics: Adolescent; Antineoplastic Agents; Busulfan; Child; Cyclophosphamide; Drug Therapy; Humans; Infant; Leukemia; Leukemia, Myeloid; Melphalan; Mercaptopurine; Multiple Myeloma; Neoplasms; Phosphorus Isotopes; Prednisone

Topics: Antibodies; Antigens; Antimetabolites; Antineoplastic Agents; Humans; Immunosuppressive Agents; Leukemia; Mercaptopurine; Methotrexate; Neoplasms; Prednisone; Uveitis; Vincristine

Topics: Antineoplastic Agents; Busulfan; Chlorambucil; Cyclophosphamide; Leukemia; Mercaptopurine; Methotrexate; Neoplasms; Prednisone; Prognosis; Triamcinolone

Topics: Aneuploidy; Bone Marrow Examination; Child; Chromosome Aberrations; Chromosome Disorders; Chromosomes; Cyclophosphamide; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Mercaptopurine; Methotrexate; Microscopy, Electron, Scanning Transmission; Neoplasms; Pathology; Prednisone

Topics: Animals; Anti-Bacterial Agents; Antineoplastic Agents; Azaserine; Carcinoma, Squamous Cell; Chelating Agents; Cortisone; Leucine; Mercaptopurine; Mice; Neoplasms; Neoplasms, Experimental; Rats; Research; Sarcoma 180; Streptomycin; Thioguanine; Transplantation

Topics: Antineoplastic Agents; Chemotherapy, Cancer, Regional Perfusion; Dactinomycin; Exudates and Transudates; Fluorouracil; Humans; Mercaptopurine; Methotrexate; Neoplasms; Nitrogen Mustard Compounds; Pericardium; Peritoneal Cavity; Pleural Effusion; Surgical Procedures, Operative; Vinblastine

Topics: Adrenal Cortex Hormones; Chlorambucil; Cyclophosphamide; Dermatitis, Exfoliative; Genetic Diseases, X-Linked; Geriatrics; Hodgkin Disease; Leukemia; Leukemia, Hairy Cell; Leukemia, Lymphoid; Lymphatic Diseases; Lymphoma; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Mercaptopurine; Methotrexate; Mycosis Fungoides; Neoplasms; Pathology; Peptide Nucleic Acids; Physiology; Sarcoma; Severe Combined Immunodeficiency

Topics: Blood Chemical Analysis; Blood Platelets; Busulfan; Child; Chromosome Aberrations; Erythrocyte Count; Hematocrit; Humans; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid; Leukocyte Count; Male; Mercaptopurine; Neoplasms; Pathology; Priapism; Splenomegaly

Topics: Adolescent; Black People; Child; Chlorambucil; Cyclophosphamide; Dactinomycin; Geriatrics; Leukemia; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Mechlorethamine; Mercaptopurine; Neoplasms; Phagocytosis; Sarcoma; Steroids; Triethylenemelamine

Topics: Antineoplastic Agents; Mechlorethamine; Mercaptopurine; Methotrexate; Neoplasms; Nitrogen Mustard Compounds; Research; Tissue Culture Techniques

Topics: Chlorambucil; Hematopoiesis; Hodgkin Disease; Humans; Lymphoma; Lymphoma, Non-Hodgkin; Mercaptopurine; Neoplasms; Paraplegia; Prednisone; Spinal Cord Compression

Topics: Alkylating Agents; Amino Acids; Aminolevulinic Acid; Aminopterin; Animals; Antineoplastic Agents; Azaguanine; Blood Chemical Analysis; Carcinoma, Ehrlich Tumor; Catalase; Copper; Folic Acid Antagonists; Hemoglobins; Hydro-Lyases; Iron; Levulinic Acids; Liver; Mercaptopurine; Mice; Neoplasms; Neoplasms, Experimental; Pharmacology; Proteins; Rats; Research

Topics: Adrenal Cortex Hormones; Antimetabolites; Antineoplastic Agents; Child; Hodgkin Disease; Humans; Infant; Leukemia; Lymphatic Metastasis; Mercaptopurine; Methotrexate; Neoplasm Metastasis; Neoplasms; Neuroblastoma; Nitrogen Mustard Compounds; Toxicology; Vincristine

Topics: Adrenal Cortex Hormones; Aminopterin; Androgens; Antimetabolites; Antineoplastic Agents; Blood Platelet Disorders; Chemotherapy, Cancer, Regional Perfusion; Chlorambucil; Cyclophosphamide; Dactinomycin; Estrogens; Fluorouracil; Geriatrics; Humans; Leukopenia; Mechlorethamine; Mercaptopurine; Neoplasms; Nitrogen Mustard Compounds; Surgical Procedures, Operative; Thiotepa; Toxicology; Vinblastine

Topics: Adrenal Cortex Hormones; Cyclophosphamide; Leukemia; Mercaptopurine; Neoplasms; Pathology; Prognosis; Vinblastine

Topics: Adenocarcinoma; Antineoplastic Agents; Aspergillus; Azaserine; Carcinoma, Bronchogenic; Chick Embryo; Glycine; Mercaptopurine; Neoplasms; Neoplasms, Experimental; Puromycin; Pyrroles; Research; Saccharomyces; Tissue Culture Techniques; Triethylenemelamine

Topics: Antigen-Antibody Reactions; Biomedical Research; Blood Group Antigens; Breast Neoplasms; Colonic Neoplasms; Escherichia coli; Francisella tularensis; gamma-Globulins; Humans; Melanoma; Mercaptopurine; Neoplasms; Pharmacology; Placebos; Skin Tests; Skin Transplantation; Transplantation Immunology

Topics: Animals; Antineoplastic Agents; Cyclophosphamide; Fluorouracil; Leukemia; Leukemia, Experimental; Melphalan; Mercaptopurine; Mice; Neoplasms; Neoplasms, Experimental; Oncogenic Viruses; Pharmacology; Research; Triethylenemelamine

Topics: Adenocarcinoma; Animals; Breast Neoplasms; Cortisone; Humans; Mammary Neoplasms, Animal; Mammary Neoplasms, Experimental; Mercaptopurine; Mice; Neoplasms; Neoplasms, Experimental; Nitrogen Mustard Compounds; Pharmacology; Puromycin; Research; Sarcoma 180; Uracil Mustard; Zymosan

Topics: Animals; Cyclophosphamide; Deuterium; Deuterium Oxide; Fluorouracil; Mercaptopurine; Mice; Neoplasms; Neoplasms, Experimental; Pharmacology; Research

Topics: Aldehydes; Anilides; Animals; Antineoplastic Agents; Cyclophosphamide; Humans; Leukemia; Leukemia L1210; Leukemia, Experimental; Leukemia, Lymphoid; Mercaptopurine; Methotrexate; Mice; Neoplasms; Neoplasms, Experimental; Pharmacology; Research; Vincristine

Topics: Adrenocorticotropic Hormone; Anti-Bacterial Agents; Antibiotics, Antitubercular; Antineoplastic Agents; Busulfan; Cortisone; Immunity; Mercaptopurine; Neoplasms; Pharmacology; Rabbits; Research

Topics: Animals; Bone Marrow Transplantation; Hematopoietic System; Leukemia; Leukemia, Experimental; Leukemia, Myeloid; Lymphoma; Mercaptopurine; Mice; Neoplasms; Neoplasms, Experimental; Organotherapy; Pharmacology; Research

Topics: Choriocarcinoma; Female; Humans; Hydatidiform Mole, Invasive; Lung Neoplasms; Mercaptopurine; Neoplasm Metastasis; Neoplasms; Pregnancy; Prognosis; Surgical Procedures, Operative; Uterine Neoplasms

Topics: Bone Marrow; Injections, Intravenous; Leukopenia; Mercaptopurine; Mice; Neoplasms; Nucleosides; Pharmacology; Purines; Pyrimidines; Research; Thioinosine; Thrombocytopenia; Toxicology

Topics: Adenocarcinoma; Blood Cell Count; Carcinoma, Renal Cell; Epoetin Alfa; Erythropoietin; Geriatrics; Humans; Kidney Neoplasms; Lung Neoplasms; Mercaptopurine; Neoplasm Metastasis; Neoplasms; Neoplasms, Second Primary; Nephrectomy

Topics: Antineoplastic Agents; Bone Neoplasms; Dactinomycin; Female; Floxuridine; Fluorouracil; Genital Neoplasms, Female; Humans; In Vitro Techniques; Intestinal Neoplasms; Leukemia; Mechlorethamine; Melanoma; Mercaptopurine; Methotrexate; Neoplasms; Pharyngeal Neoplasms; Respiratory Tract Neoplasms; Stomach Neoplasms; Thiotepa

Topics: Angiography; Choriocarcinoma; Chorion; Female; Humans; Hydatidiform Mole; Mercaptopurine; Methotrexate; Neoplasms; Pregnancy; Surgical Procedures, Operative; Uterine Neoplasms; Vinblastine

Topics: Acridines; Animals, Newborn; Anticarcinogenic Agents; Antineoplastic Agents; Cortisone; Cyclophosphamide; Immunity; Mercaptopurine; Neoplasms; Pharmacology; Quinolines; Rabbits; Research

Topics: Antineoplastic Agents; Busulfan; Child; Cyclophosphamide; Dactinomycin; Humans; Hydroxyurea; Leukemia; Leukemia, Lymphoid; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Mercaptopurine; Neoplasms; Neuroblastoma; Sarcoma; Urea

Topics: Adrenal Cortex Hormones; Adrenocorticotropic Hormone; Alkylating Agents; Anemia; Anemia, Hemolytic, Autoimmune; Busulfan; Chlorambucil; Cyclophosphamide; Folic Acid Antagonists; Hemorrhage; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Mercaptopurine; Neoplasms; Nitrogen Mustard Compounds; Phosphorus Isotopes; Splenectomy; Thioguanine; Triethylenemelamine

Topics: Allergy and Immunology; Aminopterin; Antibody Formation; Antineoplastic Agents; Cell Nucleus; Humans; Kidney Transplantation; Mercaptopurine; Neoplasms; Surgeons; Transplantation; Transplantation Immunology

Topics: Adrenal Cortex Hormones; Antineoplastic Agents; Asian People; Busulfan; DNA; DNA, Neoplasm; Epidemiology; Formates; Geriatrics; Humans; Infant; Japan; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Mercaptopurine; Mitomycin; Neoplasms; Prednisolone; RNA; RNA, Neoplasm

Topics: Animals; Bone Marrow Examination; Hemagglutination Inhibition Tests; Interferons; Leukemia; Leukemia, Myeloid; Lymph Nodes; Mercaptopurine; Neoplasms; Neutralization Tests; Newcastle disease virus; Orthomyxoviridae; Spleen; Tissue Culture Techniques; Vertebrates; Viruses

Topics: Adolescent; Child; Humans; Infant; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Mercaptopurine; Methotrexate; Neoplasms; Prednisone; Prognosis

Topics: Anti-Bacterial Agents; Antimetabolites; Antineoplastic Agents; Cortisone; Cyclophosphamide; Fluorouracil; Folic Acid Antagonists; Mechlorethamine; Mercaptopurine; Neoplasms; Toxicology

Topics: Anemia; Anemia, Myelophthisic; Blood Cell Count; Blood Sedimentation; Bone Marrow Examination; Hemorrhage; Humans; Leukemia, Promyelocytic, Acute; Mercaptopurine; Neoplasms; Pathology; Prednisone

Topics: Adrenal Cortex Hormones; Busulfan; Chlorambucil; Cortisone; Cyclophosphamide; Hodgkin Disease; Humans; Leukemia; Lymphoma; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Mechlorethamine; Mercaptopurine; Methotrexate; Neoplasms; Palliative Care; Sarcoma; Vinblastine

Topics: Air Conditioning; Antisepsis; Choriocarcinoma; Female; Hospital Design and Construction; Hospital Planning; Humans; Intensive Care Units; Mercaptopurine; Methotrexate; Neoplasms; Nursing Service, Hospital; Pregnancy

Topics: Bone Marrow Examination; Brain Neoplasms; Cerebrospinal Fluid Proteins; Humans; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Meninges; Mercaptopurine; Methotrexate; Neoplasms; Prednisone

Topics: Animals; Antineoplastic Agents; Chemistry, Pharmaceutical; Mercaptopurine; Neoplasms; Neoplasms, Experimental; Nucleosides; Pharmacology; Research; Thioinosine

Topics: Busulfan; Chlorambucil; Cyclophosphamide; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Mercaptopurine; Methotrexate; Mustard Plant; Neoplasms; Splenomegaly; Steroids; Uracil

Topics: Abnormalities, Drug-Induced; Adenine; Female; Mercaptopurine; Neoplasms; Neoplasms, Experimental; Pharmacology; Placenta; Pregnancy; Purines; Pyrazoles; Pyrimidines; Rats; Research; Teratogenesis; Thioguanine; Toxicology

Topics: Animals; Antineoplastic Agents; Carcinoma, Ehrlich Tumor; Glutaminase; Leukemia; Leukemia, Experimental; Lymphoma; Lymphoma, Non-Hodgkin; Mercaptopurine; Mice; Neoplasms; Neoplasms, Experimental; Pharmacology; Research; Sarcoma 180; Toxicology

Topics: Animals; Chemistry, Pharmaceutical; Cricetinae; Mechlorethamine; Mercaptopurine; Mice; Neoplasms; Neoplasms, Experimental; Nitrogen Mustard Compounds; Pharmacology; Rats; Research

Topics: Adrenal Cortex Hormones; Azaserine; Busulfan; Diagnosis, Differential; Drug Therapy; Humans; Leukemia; Leukemia, Erythroblastic, Acute; Leukemia, Myeloid; Liver; Lymph Nodes; Mercaptopurine; Neoplasms; Pathology; Spleen

Topics: Adenocarcinoma; Alkylating Agents; Animals; Antineoplastic Agents; Bence Jones Protein; Cecum; Cyclophosphamide; gamma-Globulins; Intestinal Neoplasms; Mechlorethamine; Mercaptopurine; Methotrexate; Mice; Multiple Myeloma; Neoplasms; Neoplasms, Experimental; Neoplasms, Plasma Cell; Pathology; Pharmacology; Prednisolone; Radiation Effects; Research

Topics: Animals; Anti-Bacterial Agents; Antibodies; Antineoplastic Agents; Blood Cells; Carcinoma, Ehrlich Tumor; Cortisone; Cytarabine; Cytosine; Leukemia L1210; Leukemia, Experimental; Lymphoma; Mercaptopurine; Methotrexate; Mice; Neoplasms; Neoplasms, Experimental; Pharmacology; Research; Sarcoma 180

Topics: Biopsy; Bone Marrow Cells; Carcinoma; Humans; Leukemia; Leukemia, Monocytic, Acute; Leukemia, Myeloid; Lymphoma; Mercaptopurine; Multiple Myeloma; Myositis; Neoplasms; Polymyositis; Prednisone; Sarcoma

Topics: Adolescent; Adrenal Cortex Hormones; Child; Drug Therapy; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Mercaptopurine; Methotrexate; Neoplasms; Prednisone

Topics: Animals; Antineoplastic Agents; Azaguanine; Culture Media; Cyclophosphamide; Dactinomycin; Drug Tolerance; Fluorouracil; Glucosamine; Histocytochemistry; In Vitro Techniques; Mechlorethamine; Mercaptopurine; Mitomycin; Mitomycins; Neoplasm Transplantation; Neoplasms; Nitrogen Mustard Compounds; Pharmacology; Rats; Research; Sarcoma; Sarcoma, Experimental; Sarcoma, Yoshida; Thiotepa; Tissue Culture Techniques

Topics: Aminopterin; Animals; Antineoplastic Agents; Azaguanine; Carboxylic Acids; Carcinoma, Ehrlich Tumor; Catalase; Cyclopentanes; Liver; Mercaptopurine; Methotrexate; Mice; N-Glycosyl Hydrolases; Neoplasms; Oxidoreductases; Thiotepa; Urate Oxidase; Xanthine Oxidase

Topics: Busulfan; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Mercaptopurine; Neoplasms; Radiotherapy

Topics: Adolescent; Alanine; Antineoplastic Agents; Child; Dexamethasone; Humans; Leukemia; Mechlorethamine; Mercaptopurine; Neoplasms; Pathology; Radiotherapy; Sarcoma, Myeloid

Topics: Acridines; Adenine; Animals; Carcinoma; Carcinoma, Ehrlich Tumor; DNA; DNA, Neoplasm; Guanine; Liver; Mercaptopurine; Mice; Neoplasms; Nucleotides; Pharmacology; Proteins; Research

Topics: Antineoplastic Agents; Brain Neoplasms; Castration; Choriocarcinoma; Female; Humans; Hydatidiform Mole, Invasive; Hysterectomy; Lung Neoplasms; Mercaptopurine; Methotrexate; Neoplasm Metastasis; Neoplasms; Pregnancy; Trophoblastic Neoplasms; Uterine Neoplasms

Topics: Animals; Antineoplastic Agents; Ascites; Busulfan; Chemical Phenomena; Chemistry; In Vitro Techniques; Mercaptopurine; Neoplasms; Nitrogen Mustard Compounds; Pharmacology; Sarcoma; Sarcoma, Yoshida

Topics: Aminopterin; Antineoplastic Agents; Azaguanine; Carbohydrate Metabolism; In Vitro Techniques; Lactates; Leukemia; Leukocytes; Mechlorethamine; Mercaptopurine; Metabolism; Neoplasms; Prednisone; Research; Thiotepa; Vinblastine

Topics: Alkylating Agents; Blood Chemical Analysis; Busulfan; Deoxyribonuclease I; DNA; Humans; Leukemia; Leukemia, Myeloid; Leukocyte Count; Mechlorethamine; Mercaptopurine; Neoplasms; Ribose

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Mercaptopurine; Mice; Neoplasms; Neoplasms, Experimental; Research; Sarcoma 180; Thioguanine; Toxicology

Topics: Adrenal Cortex Hormones; Antineoplastic Agents; Busulfan; Folic Acid Antagonists; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Mercaptopurine; Neoplasms; Nitrogen Mustard Compounds

Topics: Adrenal Cortex Hormones; Anti-Bacterial Agents; Antineoplastic Agents; Aziridines; Busulfan; Colchicine; Dactinomycin; Diethylstilbestrol; Estrogens; Fluorouracil; Gonadal Steroid Hormones; Mercaptopurine; Methotrexate; Mitomycin; Mitomycins; Neoplasms; Podophyllum; Progestins; Quinones; Thiotepa; Triethylenemelamine; Urethane; Vinblastine

Topics: Busulfan; Child; Chlorambucil; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Mercaptopurine; Neoplasms; Phosphorus Isotopes; Prednisolone; Prednisone; Urethane

Topics: Antineoplastic Agents; Busulfan; Colchicine; Early Diagnosis; Hodgkin Disease; Mechlorethamine; Mercaptopurine; Neoplasms; Phenylalanine; Podophyllum; Triethylenemelamine; Vinblastine

Topics: Adolescent; Adrenal Cortex Hormones; Anti-Bacterial Agents; Antimetabolites; Antineoplastic Agents; Blood Transfusion; Cerebral Hemorrhage; Child; Hemorrhagic Disorders; Humans; Infant; Leukemia; Leukemia, Myeloid; Mercaptopurine; Neoplasms; Photomicrography; Sepsis; Toxicology; Vitamins

Topics: Animals; Anti-Bacterial Agents; Antineoplastic Agents; Cysteine; Diethylstilbestrol; Mechlorethamine; Mercaptopurine; Mice; Neoplasms; Pharmacology; Research; Sarcoma; Sarcoma 180; Sarcoma, Experimental

Topics: Animals; Antineoplastic Agents; Chemistry, Pharmaceutical; Mercaptopurine; Mice; Neoplasms; Pharmacology; Pyrimidines; Research; Sarcoma 180

Topics: Adrenal Cortex Hormones; Aged; Bone Marrow; Busulfan; Chlorambucil; Cyclophosphamide; Hodgkin Disease; Humans; Leukemia; Lymphoid Tissue; Lymphoma; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Mercaptopurine; Methotrexate; Multiple Myeloma; Neoplasms; Sarcoma

Topics: Blood; Cytodiagnosis; Hodgkin Disease; Humans; Lymphoma; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Mercaptopurine; Neoplasms; Sarcoma; Vinblastine

Topics: Carbohydrate Metabolism; Carbohydrates; Mercaptopurine; Neoplasms

Topics: Ascites; Biochemical Phenomena; Carcinoma; Humans; Mercaptopurine; Neoplasms; Nucleosides; Nucleotides

Topics: Ascites; Biochemical Phenomena; Carcinoma; Mercaptopurine; Neoplasms; Nucleosides; Nucleotides

Topics: Allografts; Animals; Mercaptopurine; Neoplasm Transplantation; Neoplasms; Rats; Transplantation, Homologous

Topics: Leukemia; Mercaptopurine; Neoplasms

Topics: Cell Nucleus; Liver; Mercaptopurine; Neoplasms; Niacin; Niacinamide; Substrate Specificity; Transferases

Topics: Antineoplastic Agents; Chemistry Techniques, Analytical; Copper; Mechlorethamine; Mercaptopurine; Neoplasms; Nitrogen Mustard Compounds; Polarography; Uracil

Topics: Animals; Ascites; Azaserine; Azoles; Carcinoma, Ehrlich Tumor; Humans; Mercaptopurine; Neoplasms; Neoplasms, Experimental; Pyrimidines; Serine; Thioguanine

Topics: Antimetabolites; Ascites; Carcinoma; Mercaptopurine; Neoplasms; Nucleosides; Nucleotides; Purine Nucleosides

Topics: Antimetabolites; Ascites; Carcinoma; Humans; Mercaptopurine; Neoplasms; Physiological Phenomena

Topics: Animals; Azaguanine; Mercaptopurine; Neoplasms; Rats; Sarcoma

Topics: Animals; Antineoplastic Agents; Busulfan; Chlorambucil; Mercaptopurine; Neoplasms; Rats; Sarcoma

Topics: Animals; Ascites; Carcinoma, Ehrlich Tumor; Mercaptopurine; Neoplasms; Phosphates

Topics: 6-Aminonicotinamide; Adjuvants, Immunologic; Adjuvants, Pharmaceutic; Chemotherapy, Adjuvant; Drug Therapy, Combination; Mercaptopurine; Neoplasms; Neoplasms, Experimental; Niacin; Nicotinic Acids; Peptides; X-Rays

Topics: Encephalomyelitis; Humans; Mercaptopurine; Neoplasms; Thioguanine

Topics: Aminopterin; Bronchi; Bronchial Neoplasms; Carcinoma, Bronchogenic; Humans; Mercaptopurine; Neoplasms; Triethylenemelamine

Topics: Disease Management; Humans; Leukemia; Mercaptopurine; Neoplasms

Topics: Animals; Mechlorethamine; Mercaptopurine; Mice; Neoplasm Transplantation; Neoplasms; Nitrogen Mustard Compounds

Current trends in the search for chemical compounds having an inhibitory action on the growth of malignant cells are reviewed in this article. Several agents are sufficiently promising that clinical trials with them are in progress. One of these, an aromatic nitrogen mustard (C.B. 1348), appears to be useful as an adjunctive therapeutic measure in patients with malignant lymphoma, chronic lymphocytic leukemia, and mycosis fungoides who have become refractory to other methods of treatment. The introduction of certain purine antagonists, of which 6-mercaptopurine has been given the most extensive clinical trial, has opened up a new field of experimental and clinical investigation. 6-mercaptopurine and related compounds appear to be particularly useful in the treatment of acute leukemia in adults, but they are also useful, together with the folic acid antagonists and the steroid hormones, in the management of acute leukemia in children. While at present chemotherapeutic agents currently under investigation rarely cause significant regression of inoperable primary or metastatic solid tumors, the possibility of eventual more effective control in many types of malignant disease is not as dismal as it was a decade ago.

Topics: Adult; Antineoplastic Agents; Humans; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma; Mercaptopurine; Mycosis Fungoides; Neoplasms

Topics: Animals; Anti-Bacterial Agents; Ascites; Azaserine; Carcinoma, Ehrlich Tumor; Mercaptopurine; Neoplasms; Purines

Topics: Cortisone; Leukemia; Mercaptopurine; Neoplasms; Purines

Topics: Leukemia; Mercaptopurine; Mononuclear Phagocyte System; Neoplasms; Purines

Topics: Adenine; Animals; Antimetabolites; Carcinoma; Carcinoma, Squamous Cell; Humans; Mercaptopurine; Neoplasms; Neoplasms, Experimental

Topics: Animals; Mercaptopurine; Neoplasms; Neoplasms, Experimental; Purines

Topics: Humans; Mercaptopurine; Neoplasms; Neoplasms, Experimental; Purines

Topics: Mercaptopurine; Neoplasms; Purines

Topics: Leukemia; Mercaptopurine; Neoplasms; Purines

Topics: Mercaptopurine; Neoplasms; Purines

Topics: Mercaptopurine; Neoplasms; Purines

Topics: Arylsulfonates; Leukemia; Mercaptopurine; Neoplasms; Purines

Topics: Leukemia; Mercaptopurine; Neoplasms; Purines

Topics: Mercaptopurine; Neoplasms; Purines

Topics: Leukemia; Mercaptopurine; Neoplasms; Purines

Topics: Biomedical Research; Leukemia; Mercaptopurine; Neoplasms; Purines