mitoguazone and Neoplasms

The pharmacology and clinical application of three guanidino-containing compounds are reviewed in this commentary with special focus on a new member of this group of drugs, CHS 828 [N-(6-(4-chlorophenoxy)hexyl)-N'-cyano-N"-4-pyridylguanidine]. m-Iodobenzylguanidine (MIBG) and methylglyoxal bis(guanylhydrazone) (MGBG) have been extensively studied, preclinically as well as clinically, and have established use as anticancer agents. MIBG has structural similarities to the neurotransmitter, norepinephrine, and MGBG is a structural analog of the natural polyamine spermidine. CHS 828 is a pyridyl cyanoguanidine newly recognized as having cytotoxic effects when screening antihypertensive compounds. Apart from having the guanidino groups in common, there are many differences between these drugs in both structure and their mechanisms of action. However, they all inhibit mitochondrial function, a seemingly unique feature among chemotherapeutic drugs. In vitro in various cell lines and primary cultures of patient tumor cells and in vivo in various tumor models, CHS 828 has cytotoxic properties unlike any of the standard cytotoxic drugs with which it has been compared. Among these are non-cross-resistance to standard drugs and pronounced activity in tumor models acknowledged to be highly drug-resistant. Similar to MIBG, CHS 828 induces an early increase in extracellular acidification, due to stimulation of the glycolytic flux. Furthermore, ATP levels decrease, and the syntheses of DNA and protein are shut off after approximately 30 hr of exposure, indicating active cell death. CHS 828 is now in early clinical trials, the results of which are eagerly awaited.

Topics: 3-Iodobenzylguanidine; Animals; Antineoplastic Agents; Clinical Trials as Topic; Cyanides; Disease Models, Animal; Guanidines; Humans; Mitoguazone; Neoplasms

Topics: Alkaloids; Animals; Antineoplastic Agents; Azacitidine; Biphenyl Compounds; Chrysenes; Deoxycytidine; Echinomycin; Epirubicin; Etanidazole; Flavonoids; Gemcitabine; Guanidines; Humans; Idarubicin; Menogaril; Mitoguazone; Neoplasms; Nitroimidazoles; Nogalamycin; Organoplatinum Compounds; Paclitaxel; Pentostatin; Polymers; Propylene Glycols; Ribavirin; Sulfonylurea Compounds; Trimetrexate; Vidarabine Phosphate

The polyamines putrescine, spermidine and spermine represent a group of naturally occurring compounds exerting a bewildering number of biological effects, yet despite several decades of intensive research work, their exact physiological function remains obscure. Chemically these compounds are organic aliphatic cations with two (putrescine), three (spermidine) or four (spermine) amino or amino groups that are fully protonated at physiological pH values. Early studies showed that the polyamines are closely connected to the proliferation of animal cells. Their biosynthesis is accomplished by a concerted action of four different enzymes: ornithine decarboxylase, adenosylmethionine decarboxylase, spermidine synthase and spermine synthase. Out of these four enzyme, the two decarboxylases represent unique mammalian enzymes with an extremely short half life and dramatic inducibility in response to growth promoting stimuli. The regulation of ornithine decarboxylase, and to some extent also that of adenosylmethionine decarboxylase, is complex, showing features that do not always fit into the generally accepted rules of molecular biology. The development and introduction of specific inhibitors to the biosynthetic enzymes of the polyamines have revealed that an undisturbed synthesis of the polyamines is a prerequisite for animal cell proliferation to occur. The biosynthesis of the polyamines thus offers a meaningful target for the treatment of certain hyperproliferative diseases, most notably cancer. Although most experimental cancer models responds strikingly to treatment with polyamine antimetabolites--namely, inhibitors of various polyamine synthesizing enzymes--a real breakthrough in the treatment of human cancer has not yet occurred. It is, however, highly likely that the concept is viable. An especially interesting approach is the chemoprevention of cancer with polyamine antimetabolites, a process that appears to work in many experimental animal models. Meanwhile, the inhibition of polyamine accumulation has shown great promise in the treatment of human parasitic diseases, such as African trypanosomiasis.

Topics: Adenosylmethionine Decarboxylase; Animals; Biogenic Polyamines; Cell Division; Eflornithine; Humans; Mitoguazone; Neoplasms; Ornithine Decarboxylase; Ornithine Decarboxylase Inhibitors

Because of its severe side effects, initial clinical trials of the antineoplastic compound mitoguazone (Methyl-GAG, M-G) were ceased in the middle of 1960s. One decade later pharmacokinetically guided dose schedules as well as new experimental data on the antiproliferative mechanism of action stimulated new clinical studies. First results indicated that M-G had single-agent activity against various tumors such as acute leukemia and malignant lymphoma connected with acceptable tolerance. M-G seems to be effective especially in combination with other antineoplastic drugs. Its final evaluation may be reserved to further randomized trials. Recently, the psoriasis vulgaris is expected to be an additional field of the application of M-G. In this minireview data on synthesis, preclinical pharmacology, pharmacokinetics, biochemical effects and toxicology of M-G are given. Furthermore, clinical findings on M-G concerning its pharmacokinetic behaviour, antitumor and antipsoriatic activities are described.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Chemical Phenomena; Chemistry; Clinical Trials as Topic; Humans; Lethal Dose 50; Mitoguazone; Neoplasms; Psoriasis

The polyamines, putrescine, spermidine and spermine are small cationic molecules essential for DNA synthesis and cell replication. Because the cytotoxicity of most anti-cancer drugs can be attributed to inhibitory effects on DNA synthesis and cell replication it led to speculation that inhibition of polyamine synthesis could be a useful tool in the control of neoplastic growth. In 1978 alpha-difluoromethylornithine (DFMO), a powerful inhibitor of ornithine decarboxylase, the rate limiting enzyme in polyamine synthesis, was synthesized by Metcalf. Since then numerous investigators have tested the potential of DFMO and other polyamine antimetabolites as chemotherapeutic agents in experimental animals and cell cultures. The accumulated knowledge is now being evaluated in the treatment of human proliferative disorders and cancer.

Topics: Animals; Antimetabolites; Antineoplastic Agents; Body Weight; Cell Division; Cell Line; Child; Drug Interactions; Eflornithine; Female; Humans; Mice; Mitoguazone; Neoplasms; Neoplasms, Experimental; Ornithine; Ornithine Decarboxylase Inhibitors; Polyamines; Rats

Initial clinical trials of methyl-GAG (MGBG) showed that repetitive daily administration produced severe, occasionally fatal, toxic reactions. After two decades of neglect, recent studies have shown that doses of 500-600 mg/sq m administered every 7-14 days are very well tolerated. Moreover, current results indicate that MGBG has useful antitumor activity in patients with advanced malignant lymphoma and carcinomas of the head and neck, esophagus, and lung (non-small cell). The drug's mechanism of cytotoxic action and its toxic effects are not shared by most other cancer chemotherapeutic drugs. Furthermore, Phase II and Phase III evaluation are required to determine the therapeutic potential of this unique agent.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Chemical Phenomena; Chemistry; Clinical Trials as Topic; Colonic Neoplasms; Diarrhea; Dose-Response Relationship, Drug; Drug Eruptions; Drug Therapy, Combination; Eflornithine; Esophageal Neoplasms; Guanidines; Head and Neck Neoplasms; Humans; Kidney Neoplasms; Leukemia; Leukemia L1210; Lung Neoplasms; Mice; Mitoguazone; Muscular Diseases; Nausea; Neoplasms; Ornithine; Polyamines; Stilbamidines; Structure-Activity Relationship

Topics: Cell Division; Cell Transformation, Neoplastic; Chemical Phenomena; Chemistry; Humans; Lactoylglutathione Lyase; Lyases; Mitoguazone; Neoplasms; Pyruvaldehyde; Thiolester Hydrolases

Our previous studies have demonstrated the existence of synergism in a combination therapy using mitoguazone and gemcitabine when the mitoguazone is administered 24 hours before gemcitabine. Based on the cell culture and animal experimental results, a phase I clinical trial was performed in order to determine the toxicity of the combined treatment. Mitoguazone and gemcitabine were administered sequentially: mitoguazone on day 1 and gemcitabine on day 2. This cycle was repeated every 2 weeks. The dosages of these two drugs were varied between patients. Ten patients were enrolled in the study. Six patients began treatment at dose level 1 (mitoguazone 500 mg/m2, gemcitabine 1500 mg/m2), three at dose level 2 (mitoguazone 500 mg/m2, gemcitabine 2000 mg/m2), and one at dose level 3 (mitoguazone 600 mg/m2, gemcitabine 2000 mg/m2). Dose-limiting toxicity (DLT) was only observed in two patients treated at dose level 1 and one patient treated at dose level 3, while all the other patients only experienced nonhematologic toxicity, such as asthenia and mucositis. Two melanoma patients showed responses (one partial and one minor) to the treatment. One lymphoma patient also showed a brief partial response. This phase I trial indicated that the combination of mitoguazone and gemcitabine had limited but noticeable activity for treatment of cancer patients. Further study on the toxicity and on the effect of the scheduled mitoguazone-gemcitabine combination is needed.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Gemcitabine; Humans; Infusions, Intravenous; Male; Middle Aged; Mitoguazone; Neoplasms

Because of its severe side effects, initial clinical trials of the antineoplastic compound mitoguazone (Methyl-GAG, M-G) were ceased in the middle of 1960s. One decade later pharmacokinetically guided dose schedules as well as new experimental data on the antiproliferative mechanism of action stimulated new clinical studies. First results indicated that M-G had single-agent activity against various tumors such as acute leukemia and malignant lymphoma connected with acceptable tolerance. M-G seems to be effective especially in combination with other antineoplastic drugs. Its final evaluation may be reserved to further randomized trials. Recently, the psoriasis vulgaris is expected to be an additional field of the application of M-G. In this minireview data on synthesis, preclinical pharmacology, pharmacokinetics, biochemical effects and toxicology of M-G are given. Furthermore, clinical findings on M-G concerning its pharmacokinetic behaviour, antitumor and antipsoriatic activities are described.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Chemical Phenomena; Chemistry; Clinical Trials as Topic; Humans; Lethal Dose 50; Mitoguazone; Neoplasms; Psoriasis

Initial clinical trials of methyl-GAG (MGBG) showed that repetitive daily administration produced severe, occasionally fatal, toxic reactions. After two decades of neglect, recent studies have shown that doses of 500-600 mg/sq m administered every 7-14 days are very well tolerated. Moreover, current results indicate that MGBG has useful antitumor activity in patients with advanced malignant lymphoma and carcinomas of the head and neck, esophagus, and lung (non-small cell). The drug's mechanism of cytotoxic action and its toxic effects are not shared by most other cancer chemotherapeutic drugs. Furthermore, Phase II and Phase III evaluation are required to determine the therapeutic potential of this unique agent.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Chemical Phenomena; Chemistry; Clinical Trials as Topic; Colonic Neoplasms; Diarrhea; Dose-Response Relationship, Drug; Drug Eruptions; Drug Therapy, Combination; Eflornithine; Esophageal Neoplasms; Guanidines; Head and Neck Neoplasms; Humans; Kidney Neoplasms; Leukemia; Leukemia L1210; Lung Neoplasms; Mice; Mitoguazone; Muscular Diseases; Nausea; Neoplasms; Ornithine; Polyamines; Stilbamidines; Structure-Activity Relationship

The anticancer activity of DNA intercalators is related to their ability to intercalate into the DNA duplex with high affinity, thereby interfering with DNA replication and transcription. Polyamines (spermine in particular) are almost exclusively bound to nucleic acids and are involved in many cellular processes that require nucleic acids. Until now, the effects of polyamines on DNA intercalator activities have remained unclear because intercalation is the most important mechanism employed by DNA-binding drugs. Herein, using actinomycin D (ACTD) as a model, we have attempted to elucidate the effects of spermine on the action of ACTD, including its DNA-binding ability, RNA and DNA polymerase interference, and its role in the transcription and replication inhibition of ACTD within cells. We found that spermine interfered with the binding and stabilization of ACTD to DNA. The presence of increasing concentrations of spermine enhanced the transcriptional and replication activities of RNA and DNA polymerases, respectively, in vitro treated with ActD. Moreover, a decrease in intracellular polyamine concentrations stimulated by methylglyoxal-bis(guanylhydrazone) (MGBG) enhanced the ACTD-induced inhibition of c-myc transcription and DNA replication in several cancer cell lines. The results indicated that spermine attenuates ACTD binding to DNA and its inhibition of transcription and DNA replication both in vitro and within cells. Finally, a synergistic antiproliferative effect of MGBG and ACTD was observed in a cell viability assay. Our findings will be of significant relevance to future developments in combination with cancer therapy by enhancing the anticancer activity of DNA interactors through polyamine depletion.

Topics: Antineoplastic Agents; Bacteriophage T7; Cell Line, Tumor; Dactinomycin; DNA; DNA Polymerase I; DNA Replication; DNA-Directed RNA Polymerases; Escherichia coli; Humans; Intercalating Agents; Mitoguazone; Models, Molecular; Neoplasms; Spermine; Transcription, Genetic

The design and synthesis of antitumor imidazothiazole guanylhydrazones are reported. The compounds were submitted to NCI for testing. All but one were more active than methyl-GAG. A few compounds were selected for further studies in search of a possible mechanism of action. The results from these studies and a final search with the NCI COMPARE algorithm suggest that the guanylhydrazones described in this paper are acting through a novel mechanism of action.

Topics: Adenosylmethionine Decarboxylase; Antineoplastic Agents; Cell Cycle; Cell Death; Drug Screening Assays, Antitumor; HL-60 Cells; Humans; Hydrazones; Membrane Potential, Mitochondrial; Molecular Structure; Neoplasms; Structure-Activity Relationship; Thiazoles; Tumor Cells, Cultured

Unfortunately, the vast majority (90%) of new anticancer agents designed in the laboratory never make it into routine clinical use. The hypothesis of this lecture is that many new agents fail in the clinic because the appropriate clinical trial(s) that could exploit the attributes of the new agent are not performed. An appreciation that both bench and clinical investigations are difficult endeavors should aid in improving clinical trial designs and give the best chance for new agents to be added to our therapeutic armamentarium.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents; Clinical Trials as Topic; Deoxycytidine; Eflornithine; Gemcitabine; Humans; Mitoguazone; Neoplasms; Research Design

alpha-Difluoromethylornithine (DFMO) is a potent inhibitor of the synthesis of putrescine (pu) and spermidine (sd) in some benign and malignant tissues. Intracellular deprivation of pu and sd has been shown to induce an enhanced uptake of polyamine-analogs such as methyl-GAG (MGBG). The purpose of this study was to investigate the tolerance and the toxicity of the combination of DFMO and MGBG. Thirty-six patients received 4 X 2 g of DFMO/day orally and every 2 weeks 250-500 mg/m2 of MGBG as a 2-hr infusion, starting on day 14. Besides the well known acute and late side-effects of methyl-GAG, dose-limiting toxicity consisted also of thrombocytopenia, leucopenia, dyspnea, hemolysis and jaundice. The maximal tolerated dose of MGBG for one course was 350 mg/m2 and for repeated courses 250 mg/m2, due to cumulative toxicity. Furthermore, after 8 weeks of continuous administration of DFMO 70% of the patients had a severe hearing loss, which was reversible after a treatment delay of 4-6 weeks. Since the hearing loss prohibited the continuous use of DFMO, two different schedules of intermittent DFMO-administration together with two different infusion periods of MGBG have been investigated in 15 patients. In none of these patients did hearing loss occur. The schedule of continuous administration of 4 X 2 g of DFMO/day orally for 21 days and 250 mg/m2 of MGBG as a 24-hr infusion on days 7, 14 and 21, repeated on day 42, was tolerated best. In 28 evaluable patients two partial remissions were seen. Pretreatment with DFMO significantly enhanced the toxicity of MGBG and the combination of both drugs produced side-effects not seen with either drug alone.

Topics: Adolescent; Adult; Aged; Anemia, Hemolytic; Antineoplastic Combined Chemotherapy Protocols; Deafness; Drug Evaluation; Eflornithine; Humans; Leukopenia; Middle Aged; Mitoguazone; Neoplasms; Ornithine; Thrombocytopenia

Topics: Animals; Antineoplastic Agents; Cell Cycle; DNA Repair; Drug Therapy, Combination; Eflornithine; Humans; Mitoguazone; Neoplasms; Ornithine; Ornithine Decarboxylase Inhibitors; Polyamines; Sister Chromatid Exchange

Both DFMO and methyl-GAG inhibit sequential enzymatic reactions in the pathway of polyamine biosynthesis. Since polyamines may be important factors in proliferation of cancer cells, we initiated a phase-I study of these agents in patients with advanced cancer. DFMO was given by mouth at a constant daily dose of 4 g/m2 starting on day 1 of the treatment protocol. The dose of methyl-GAG ranged from 200 to 700 mg/m2 administered IV every 2 weeks beginning on day 4. Twenty-two patients were entered into the protocol. Toxic reactions to this therapy were dose-related and included nausea, fatigue, diarrhea, and myelosuppression. One patient with colon cancer experienced a greater than 50% decrease in measurable disease but developed severe myelotoxicity. While DFMO was well tolerated, the combination of drugs appeared to cause substantially more hematologic and gastrointestinal toxicity than encountered during our recent experience with methyl-GAG used alone. We suggest that future studies of this drug combination carefully evaluate levels of polyamines and inhibition of enzymatic activity to minimize toxicity.

Topics: Adult; Aged; Antineoplastic Agents; Drug Evaluation; Drug Therapy, Combination; Eflornithine; Guanidines; Humans; Middle Aged; Mitoguazone; Neoplasms; Ornithine; Polyamines

Methyl-GAG was given to 71 patients with advanced malignancies as a weekly brief infusion (30-120 minutes) or as a biweekly 24- or 120-hour infusion. Mucositis (stomatitis, pharyngitis, esophagitis, and, rarely, inflammation of other mucous membranes) was dose-limiting in all three schedules. Generalized fatigue, malaise, myalgia, dysesthesias, nausea, and vomiting were more frequent in the brief-infusion schedule. Myelosuppression was mild and not dose-related. Fever, ventricular arrhythmias, skin rash, tender swelling of the palms, neuropathy, and paralytic ileus were rare. Toxicity was increased in patients with renal insufficiency or "third-space" fluid but was not increased by hepatic dysfunction. Cumulative and overlapping toxicity was evident only in the weekly schedule. Higher doses of methyl-GAG were tolerated when the duration of infusion was increased. The recommended doses for phase II trials are 700 mg/m2 weekly as a 1-2 hour infusion, 850 mg/m2/24 hours biweekly, and 1500 mg/m2/120 hours biweekly. Therapeutic effects were seen in all schedules and included objective responses in colon carcinoma (one of 13 patients), renal cell carcinoma (one of nine), and Hodgkin's lymphoma (one of two) and objective improvements in esophageal carcinoma (one of three), endometrial carcinoma (two of two), and leiomyosarcoma (one of three).

Topics: Adult; Aged; Antineoplastic Agents; Drug Evaluation; Female; Guanidines; Humans; Male; Middle Aged; Mitoguazone; Neoplasms

Topics: Adult; Antineoplastic Agents; Burns; Carmustine; Child; Cisplatin; Evaluation Studies as Topic; Female; Humans; Hyperthermia, Induced; Hypotension; Male; Middle Aged; Mitoguazone; Neoplasms; Nervous System Diseases

Fourteen patients with metastatic renal cell carcinoma received methyl-G weekly at a starting dose of 600 mg/m2 (five patients) and 500 mg/m2 (nine patients) intravenously. All 14 patients are evaluable for response and toxicity. No antitumor responses were observed. Six patients achieved stabilization of disease for 8 to 42 weeks. Toxicity was nonhematologic and included nausea or vomiting (35%), fever with shaking chills (28%), diarrhea (21%), myalgia (63%), paresthesia (49%), and bilateral foot drop (7%). Methyl-G does not appear to have activity against renal cell carcinoma.

Topics: Adenocarcinoma; Adult; Aged; Dose-Response Relationship, Drug; Drug Evaluation; Drug Resistance; Female; Guanidines; Humans; Male; Middle Aged; Mitoguazone; Nausea; Neoplasm Metastasis; Neoplasms; Paresthesia; Vomiting

The effect of methylglyoxal-bis-guanylhydrazone has been studied on the electrophoretic mobility of blood cells of 10 unselected and untreated patients with preferably solid malignant diseases. Prior to the incubation with CH3-G the electrophoretic mobility of lymphocytes and erythrocytes showed increased and of platelets showed decreased rates which extend over a larger range than usual and for which reasons cannot be given till now. The incubation with CH3-G caused a concentration-dependent reduction of the electrophoretic mobility of all three tested types of blood cells. This can be estimated as an impairment of a function of surface membrane and confirms recently obtained results of activity of CH3-G on platelets' surface membrane.

Topics: Blood Cells; Blood Platelets; Erythrocytes; Female; Guanidines; Humans; Lymphocytes; Male; Mitoguazone; Neoplasms

Topics: Antineoplastic Agents; Chemistry, Pharmaceutical; Guanidine; Guanidines; Mitoguazone; Neoplasms; Neoplasms, Experimental; Pharmacology; Pyruvaldehyde; Research; Spectrum Analysis

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Chemistry, Pharmaceutical; Guanidines; Hydrazines; Leukemia L1210; Leukemia, Experimental; Mitoguazone; Neoplasms; Neoplasms, Experimental; Pharmacology; Pyruvaldehyde; Research; Sarcoma 180