zinostatin and Neoplasms

Nanoclusters (NCs) are meticulously small, kinetically stable, crystalline materials which hold immense potential as multifaceted catalysts for a broad range of biomedical applications. Metal NCs are atomically precise and exist within the range of Fermi wavelength of electrons. They are highly advantageous as functional materials as their physicochemical properties can be customized to meet specific requirements. Copper NCs (CuNCs) are emerging as an efficient substitute to the other existing metal NCs. The synthesis of CuNCs is highly methodical, fast, cost effective and does not involve any complicated manipulation. On the contrary to gold and silver NCs, copper is a vital trace element for humans that can be excreted easily out the body. Further, the relatively inexpensiveness and easy availability of copper aids in potential nanotechnological applications in large quantity. As such, CuNCs have attracted great interest among the research community recently. The modern developments in the strategy, synthesis, surface modifications, and use of CuNCs in diagnosis of disease, imaging and treatment have been discussed in the present review. Approaches to regulate and augment the emission of CuNCs, challenges and drawbacks have also been considered. This review brings to light the multifarious applications of CuNCs and their potential as emerging theranostic agents. It is anticipated that the visions and directions for translating existing developments in CuNCs from the laboratory to the clinic can be further improved and enhanced.

Topics: Ambulatory Care Facilities; Copper; Diagnostic Imaging; Humans; Neoplasms; Trace Elements; Zinostatin

The enhanced permeability and retention (EPR) of nanoparticles in tumors has long stood as one of the fundamental principles of cancer drug delivery, holding the promise of safe, simple and effective therapy. By allowing particles preferential access to tumors by virtue of size and longevity in circulation, EPR provided a neat rationale for the trend toward nano-sized drug carriers. Following the discovery of the phenomenon by Maeda in the mid-1980s, this rationale appeared to be well justified by the flood of evidence from preclinical studies and by the clinical success of Doxil. Clinical outcomes from nano-sized drug delivery systems, however, have indicated that EPR is not as reliable as previously thought. Drug carriers generally fail to provide superior efficacy to free drug systems when tested in clinical trials. A closer look reveals that EPR-dependent drug delivery is complicated by high tumor interstitial fluid pressure (IFP), irregular vascular distribution, and poor blood flow inside tumors. Furthermore, the animal tumor models used to study EPR differ from clinical tumors in several key aspects that seem to make EPR more pronounced than in human patients. On the basis of this evidence, we believe that EPR should only be invoked on a case-by-case basis, when clinical evidence suggests the tumor type is susceptible.

Topics: Animals; Antineoplastic Agents; Drug Carriers; History, 20th Century; Humans; Maleic Anhydrides; Nanoparticles; Neoplasms; Permeability; Polystyrenes; Zinostatin

Tumor targeting therapy, that is "Missile therapy", using a complex composed of a tumor suppressive drug and a whole antibody against tumor cells, is expected to become an attractive chemotherapy strategy. However, clinically convincing results have not yet been obtained mainly due to poor transport from the circulation to tumor tissue and marked toxicity. Recently, recombinant immunotoxins, composed of an Fv fragment of an antibody to a tumor-related antigen fused to various truncated toxins have been developed to overcome the distribution of immunotoxins in tumors. These recombinant immunotoxins have shown encouraging clinical results for some hematopoietic malignancies. However, there were no significant anti-tumor responses to many tumors, especially solid tumors, probably due to their rapid clearance from the circulation and their immunogenicity and antigenicity. More recently, PEGylation of recombinant immunotoxins has been attempted to overcome these drawbacks. It was found that PEGylation of recombinant immunotoxins improves their effectiveness. We discuss the recent progress in tumor missile therapy. In contrast to others, we developed "Missile therapy against tumor blood vessels" by using specific monoclonal antibodies against tumor endothelial cells rather than actual tumor cells. The complex between antibodies to tumor vascular endothelial cells and anti-tumor drugs can freely access the target cells without concern for their vascular permeability. These preparations have exhibited excellent anti-tumor effects for solid tumors. In this review, we also discuss this vascular targeting therapy as an attractive new strategy for tumor chemotherapy.

Topics: Animals; Antibodies, Monoclonal; Endothelial Cells; Humans; Immunoconjugates; Immunotoxins; Interleukin-6; Neoplasms; Polyethylene Glycols; Recombinant Proteins; Zinostatin

Both enhanced vascular permeability and angiogenesis of tumor sustain rapid growth of tumor involving many vascular mediators and high vascular density. On the contrary, however, they can be utilized for macromolecular drug delivery to tumor. Impaired reticuloendothelial/lymphatic clearance of macromolecules from the tumor, or lack of such clearance, is another unique characteristic of tumor tissue, which results intratumor retention of macromolecular drugs thus delivered (Figure 1). Consequently, enhanced permeability and retention (EPR) effect is the basis for the selective targeting of macromolecular drugs to tumor, and the EPR concept is now utilized for selective delivery of many macromolecular anticancer agents in aqueous formation for i.v. or i.a. as well as oily formation for i.a. dosing, which is not possible for low-molecular-weight drugs because of rapid washout by capillary vascular blood flow. This EPR concept has been validated in clinical settings with hepatoma and other solid tumors. In our laboratories, several promising macromolecular anticancer drugs after SMANCS, such as PEG-XO, PEG-DAO, PEG-ZnPP, were developed, warranting further investigation for clinical application. More efficient drug delivery to tumor, especially of macromolecular drugs, may be possible by enhancing the EPR effect with the use of various vascular permeability mediators or potentiators. Suppression of the EPR effect by the use of appropriate inhibitors or antidotes, such as the bradykinin antagonist HOE 140 and protease inhibitors or NOS inhibitors, may also be possible. Thus, one may be able to suppress or retard tumor growth and tumor metastasis. Also, by suppressing vascular permeability with antidotes such as the bradykinin antagonist HOE 140, pleural fluid in lung cancer and ascitic fluid in abdominal carcinomatosis may be controlled and the clinical course of cancer patients may be improved. In summary, tumor vasculature can be an excellent target for delivery of macromolecular anticancer drugs; the most beneficial class of drugs in view of tumor-selective targeting based on the EPR effect in solid tumor as well as compliance of patients and ultimate therapeutic efficacy.

Topics: Amino Acid Sequence; Antineoplastic Agents; Capillary Permeability; Humans; Inflammation Mediators; Maleic Anhydrides; Molecular Sequence Data; Neoplasms; Polystyrenes; Regional Blood Flow; Vasoconstrictor Agents; Zinostatin

Recent studies have revealed that the targeting therapy using monoclonal antibody against tumor associated antigens did not have a clinically satisfactory effect due to various physiological characters of tumor. We propose a novel approach targeting tumor vascular endothelium to solve the inefficiency of common tumor missile therapy. In this study, the tissue distribution of anti-tumor vascular endothelium monoclonal antibody (TES-23) produced by immunizing with plasma membrane vesicles obtained from isolated rat tumor-derived endothelial cells (TECs) was assessed in various tumor-bearing animals. Radiolabeled TES-23 dramatically accumulated in KMT-17 fibrosarcoma, a source of isolated TECs after intravenous injection. In Meth-A fibrosarcoma, Colon-26 adenocarcinoma in BALB/c mice and HT-1080 human tumor tissue in nude mice, radioactivities of 125I-TES-23 were also up to fifty times higher than those of control antibody with little distribution to normal tissues. Furthermore, immunostaining of human tissue sections showed specific binding of TES-23 on endothelium in esophagus and colon cancers. These results indicate that tumor vascular endothelial cells express a common antigen in different tumor types of various animal species. In order to clarify the efficacy of TES-23 as a drug carrier, an immunoconjugate, composed of TES-23 and neocarzinostatin, was tested for its antitumor effect in vivo. The immunoconjugate (TES-23-NCS) caused a marked regression of the tumor, KMT-17 in rats and Meth-A in mice. Thus, from a clinical view, TES-23 would be a novel drug carrier because of its high specificity to tumor vascular endothelium and its application to many types of cancer.

Topics: Animals; Antibiotics, Antineoplastic; Antibodies, Monoclonal; Drug Carriers; Drug Delivery Systems; Endothelium, Vascular; Humans; Immunoconjugates; Mice; Neoplasms; Rats; Zinostatin

The biodistribution of soluble macromolecules is governed extensively by their ability to penetrate endothelial layers. Many solid tumors possess vasculature that is hyperpermeable to macromolecules, not always correlating with the presence of interendothelial cell fenestrations. The exact physiological mechanisms responsible for this nonspecific leakiness are not yet fully understood. Together with enhanced vascular permeability, however, tumors usually lack effective lymphatic drainage; consequently, they selectively accumulate circulating macromolecules (up to 10% of an i.v. dose per gram in mice). This "enhanced permeability and retention effect" (EPR effect) has been studied extensively, and it is thought to constitute the mechanism of action of SMANCS (styrene-maleic/anhydride-neocarzinostatin), now in regular clinical use in Japan for the treatment of hepatoma. It seems likely that EPR also contributes to the anticancer activity of the N-(2-hydroxypropyl)methacrylamide copolymer-anthracycline conjugates which are shortly to undergo clinical evaluation in the U.K.

Topics: Antineoplastic Agents; Doxorubicin; Drug Delivery Systems; Humans; Lymphatic System; Maleic Anhydrides; Mitomycins; Neoplasms; Polystyrenes; Prodrugs; Solubility; Tissue Distribution; Zinostatin

The rationale for the use of antibodies as carriers of cancer chemotherapeutic agents is based upon: the presence on cells of tumor-associated cell surface antigens (TAA); the ability to obtain specific polyclonal or monoclonal antibodies against them; and the availability of methods for binding appropriate toxic agents or radionuclides with retention of activity of both antibody and agents. The general finding so far has been that both conventional polyclonal and hybridoma-derived monoclonal antibodies can deliver cytocidal amounts of toxic agents to target tumor cells both in vitro and in vivo. Moreover, various agents with different modes of antitumor activity (e.g., DNA intercalation or alkylation, enzyme inhibition, and cell surface modification) have all produced superior tumor inhibition in conjugate form compared to the individual or synergistic inhibition produced by agent and antibody. Recent studies are contributing to the understanding of the mechanism of action of drug-antibody conjugates and are thus establishing guidelines for this approach to cancer therapy.

Topics: Antibiotics, Antineoplastic; Antibodies, Monoclonal; Antibody Specificity; Antigens, Neoplasm; Bleomycin; Chlorambucil; Humans; Immunotoxins; Mitomycin; Mitomycins; Naphthacenes; Neoplasms; Protein Binding; Radioisotopes; Species Specificity; Structure-Activity Relationship; Vindesine; Zinostatin

Topics: Animals; Antineoplastic Agents; Drug Evaluation; Humans; Injections, Intra-Arterial; Iodized Oil; Liver Neoplasms; Maleic Anhydrides; Neoplasms; Polystyrenes; Rabbits; Zinostatin

This article describes the properties and biological actions of the antitumor protein neocarzinostatin which stands for a whole group of high molecular weight antitumor antibiotics. Special emphasis is given to the development of our understanding of the molecular mechanism of neocarzinostatin action. From this mechanism of action far-reaching perspectives concerning the clinical application of neocarzinostatin are discussed.

Topics: Amino Acid Sequence; Antibiotics, Antineoplastic; Chemistry, Pharmaceutical; Drug Stability; Humans; Neoplasms; Zinostatin

This article describes previous studies on a unique protein antitumor antibiotic, neocarzinostatin. Namely, its chemical nature, mode of action at molecular and cellular levels, toxicity and pharmacology, and recent results in clinical trials obtained primarily in Japan have been reviewed briefly.

Topics: Amino Acid Sequence; Animals; Antibiotics, Antineoplastic; Clinical Trials as Topic; DNA, Neoplasm; Dogs; Drug Evaluation; Humans; Lethal Dose 50; Leukemia; Mice; Neoplasms; Rabbits; Rats; Zinostatin

Topics: Animals; Antibiotics, Antineoplastic; Bone Marrow; Digestive System; DNA, Single-Stranded; Drug Evaluation; Drug Evaluation, Preclinical; Humans; Leukemia; Neoplasms; Neoplasms, Experimental; Zinostatin

After presentation of several important methodological problems in the development of new cytostatic agents, the newer substances adriamycin, the nitroso-urea derivatives, ICDT, diaminodichloro-cisplatinum, VP 16-213 and tamoxifen are briefly discussed with regard to their pharmacology and activity spectra. In this context adriamycin, diaminochloro-cisplatinum and VP 16-213 may be considered break-throughs in the field of therapeutic oncology. Finally, several newer drugs still in phase I studies are mentioned.

Topics: Alkylating Agents; Altretamine; Antimetabolites, Antineoplastic; Cisplatin; Dacarbazine; Doxorubicin; Drug Evaluation; Drug Evaluation, Preclinical; Etoposide; Humans; Neoplasms; Nitrosourea Compounds; Razoxane; Tamoxifen; Vinca Alkaloids; Zinostatin

Neocarzinostatin (NCS) is an antibiotic from streptomyces carzinostaticus which inhibits DNA synthesis. Clinical trials in Japan began in 1971. NCS is active against S-180, Ehrlich tumor, L1210, Yoshida sarcoma, and a range of ascitic hepatomas. In rabbit NCS is distributed at high concentrations in the kidney, skin, stomach, pancreas, lung, and muscles. The high distribution in the pancreas and the stomach suggested possible effectiveness in human tumors at these sites. In clinical studies NCS has been shown to be active against acute leukemia. As a single agent 9 out of 51 obtained a CR with 9 more achieving a PR. Anorexia, nausea, and vomiting were the most frequent side effects. NCS has been tried in combination with Ara-C, daunorubicin and prednisolone and CR was ssen in 11 out of 14. In stomach cancer responses of some kind were observed in 12 out of 141 cases, while in the case of pancreatic tumors there were 10 out of 68.

Topics: Antibiotics, Antineoplastic; Drug Therapy, Combination; Japan; Kinetics; Leukemia; Neoplasms; Pancreatic Neoplasms; Stomach Neoplasms; Urinary Bladder Neoplasms; Zinostatin

Neocarzinostatin is a new anticancer drug developed by Japanese investigators. In order to delineate the potential usefulness of this drug, we have reviewed the preclinical data and summarized the Japanese clinical data on 462 patients. The bulk of these patients had carcinoma of the stomach or pancreas and acute leukemia. Neocarzinostatin was administered intravenously in a daily dose of 2-3 mg for five to 15 day periods. Significant antitumor activity was observed in acute leukemia. A few responses were also reported in pancreatic adenocarcinoma, but the drug was inactive against gastric carcinoma. The side effects observed included nausea, vomiting, myelosuppression, fever, and occasional hypersensitivity reactions. The Investigational Drug Branch of the National Cancer Institute has recently sponsored an investigational new drug application with the Food and Drug Administration, and phase I studies are expected to begin soon in the United States.

Topics: Amino Acids; Animals; Antibiotics, Antineoplastic; Cell Division; Chemical Phenomena; Chemistry; Diarrhea; DNA Replication; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Eruptions; Fever; Humans; Hypotension; Kidney Diseases; Leukopenia; Molecular Weight; Nausea; Neoplasms; Neoplasms, Experimental; Temperature; Templates, Genetic; Thrombocytopenia; Zinostatin

A phase I clinical study by intravenous injection of zinostatin stimalamer (YM 881), a protein anti-cancer drug, was conducted in 50 patients with malignant tumors. The initial dose was 0.5 mg/m2 (n) in the single dose test, and 0.2 mg/m2/day in the repeated dose test for 5 successive days. Doses were increased up to 12n according to the modified Fibonacci's method in both the single and repeated dose tests. The dose limiting factor was thrombopenia in both the single and repeated dose tests. The maximum tolerated dose was 6.0 mg/m2 (12n) in the single dose test, and the subtoxic dose was 2.4 mg/m2/day in the five day repeated dose study. These results indicate that dose of 1.0 to 1.4 mg/m2/day (5 n to 7 n) are appropriate for the phase II repeated dose study.

Topics: Adult; Aged; Drug Administration Schedule; Drug Evaluation; Female; Humans; Injections, Intravenous; Male; Maleic Anhydrides; Middle Aged; Neoplasms; Polystyrenes; Thrombocytopenia; Zinostatin

An early phase II multicentered study of YM 881 (zinostatin stimalamer) was conducted in 36 patients to investigate response and the safety of the drug in malignant tumors. The response could be evaluated in 18 patients, one with brain tumor, 2 with lung cancer, one with breast cancer, one with liver cancer, one with pancreatic cancer, 6 with gastric cancer, and 6 with colon cancer. PR was found in the patient with brain tumor. Major subjective unwanted effects were gastrointestinal symptoms. Objective evidence of hematological changes (thrombocytopenia, decreased hematocrit, and lymphocytopenia) was also obtained.

Topics: Adult; Aged; Anorexia; Brain Neoplasms; Drug Evaluation; Female; Humans; Injections, Intravenous; Lung Neoplasms; Male; Maleic Anhydrides; Middle Aged; Neoplasms; Polystyrenes; Stomach Neoplasms; Thrombocytopenia; Vomiting; Zinostatin

This article describes previous studies on a unique protein antitumor antibiotic, neocarzinostatin. Namely, its chemical nature, mode of action at molecular and cellular levels, toxicity and pharmacology, and recent results in clinical trials obtained primarily in Japan have been reviewed briefly.

Topics: Amino Acid Sequence; Animals; Antibiotics, Antineoplastic; Clinical Trials as Topic; DNA, Neoplasm; Dogs; Drug Evaluation; Humans; Lethal Dose 50; Leukemia; Mice; Neoplasms; Rabbits; Rats; Zinostatin

Cellular systems show a wide range of signaling dynamics. Many of these dynamics are highly stereotyped, such as oscillations at a fixed frequency. However, most studies looking at the role of signaling dynamics focus on one or a few cell lines, leaving the diversity of dynamics across tissues or cell lines a largely unexplored question. We focused on the dynamics of the tumor suppressor protein p53, which regulates cell cycle arrest and apoptosis in response to DNA damage. We established live-cell reporters for 12 cancer cell lines expressing wild-type p53 and quantified p53 dynamics in response to double-strand break-inducing DNA damage. In many of the tested cell lines, we found that p53 abundance oscillated in response to ionizing radiation or the DNA-damaging chemotherapeutic neocarzinostatin and that the periodicity of the oscillations was fixed. In other cell lines, p53 abundance dynamically changed in different ways, such as a single broad pulse or a continuous induction. By combining single-cell assays of p53 signaling dynamics, small-molecule screening in live cells, and mathematical modeling, we identified molecules that perturbed p53 dynamics and determined that cell-specific variation in the efficiency of DNA repair and the activity of the kinase ATM (ataxia-telangiectasia mutated) controlled the signaling landscape of p53 dynamics. Because the dynamics of wild-type p53 varied substantially between cell lines, our study highlights the limitation of using one line as a model system and emphasizes the importance of studying the dynamics of other signaling pathways across different cell lines and genetic backgrounds.

Topics: Antibiotics, Antineoplastic; Apoptosis; Ataxia Telangiectasia Mutated Proteins; Cell Line, Tumor; DNA Damage; DNA Repair; Gene Expression Regulation, Neoplastic; Humans; Mutation; Neoplasms; Phosphorylation; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-mdm2; Radiation, Ionizing; Signal Transduction; Small Molecule Libraries; Tumor Suppressor Protein p53; Zinostatin

The aim of this study was to investigate the role of Neocarzinostatin (NCS) conjugated with epithelial cell adhesion molecule (EpCAM) aptamer in EpCAM-positive cancer cells. NCS is an antitumor antibiotic protein chromophore that has the ability to cleave double stranded DNA and can be used as a potential drug for the treatment of EpCAM-positive cancers. EpCAM aptamer is an oligonucleotide ligand that binds specifically to EpCAM, a protein overexpressed in tumor cells.. NCS was conjugated with EpCAM aptamer using Sulfo-Succinimidyl 6-(3-(2-pyridyldithio) - propionamide hexanoate) LC-(SPDP) cross-linker to deliver it to EpCAM-positive tumor cells. The conjugates were characterized using polyacrylamide gel electrophoresis (PAGE) and high-performance liquid chromatography (HPLC). Flow cytometry was used to study the binding efficiency of the aptamer and the conjugates in cancer cells. The effect of the conjugate on cancer cells was studied using propidium iodide (PI) to analyze the cell cycle phase changes. The apoptosis assay was performed using the IC. Flow cytometry revealed significant binding of aptamer and conjugate in the MCF-7 and WERI-Rb1 cell lines. Briefly, 62% in MCF and 30% in WERI-Rb1 cells with conjugate treated cells (p<0.005). The cell-cycle analysis indicated G. The EpCAM aptamer conjugated NCS showed specificity to EpCAM-positive cells. The effect of the conjugates on cancer cells were impressive as the conjugate arrested the cell cycle and promoted apoptosis and necrosis. The high levels of PARP expression confirmed the DNA breaks upon conjugate treatment. Our study demonstrates that the NCS conjugated with EpCAM can be targeted to cancer cells sparing normal cells.

Topics: Antibiotics, Antineoplastic; Apoptosis; Cell Cycle; Cell Line, Tumor; DNA Breaks, Double-Stranded; DNA Damage; Epithelial Cell Adhesion Molecule; Humans; MCF-7 Cells; Neoplasms; Oligonucleotides; Zinostatin

The purpose of this study is to evaluate the improved method of arterial infusion therapy of SMANCS (SX) with lipiodol under the angiotensin-induced hypertensive state for various difficult-to-treat solid tumors. Most patients were unresectable with no other therapeutic options, recurrence after resection, or patients do not respond to common treatments. The new method utilizes angiotensin II (AT) to induce hypertension (e.g. approximately 15-30 mmHg above norm) for 15-20 min. This method was successfully applied to metastatic liver cancer, cholangiocarcinoma, massive renal cell carcinoma, pancreatic and other abdominal solid cancers. This AT-induced hypertension resulted in remarkably enhanced tumor delivery accompanied by improved therapeutic response, and a shorter time to achieve 50% regression of tumor size with least toxicity. We demonstrated clinically herein improved therapy for various advanced solid tumors with SX by elevating the tumor blood flow selectively. This is the first clinical proof that modulations of vascular pathophysiology can uniquely accomplish enhanced tumor selective delivery of polymeric drugs and thus yielded better clinical outcome.

Topics: Adenocarcinoma; Adult; Aged; Angiotensin II; Antineoplastic Agents; Blood Pressure; Carcinoma, Renal Cell; Cholangiocarcinoma; Drug Delivery Systems; Female; Humans; Hypertension; Infusions, Intravenous; Japan; Kidney Neoplasms; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Neoplasm Staging; Neoplasms; Ovarian Neoplasms; Pancreatic Neoplasms; Polystyrenes; Vasoconstrictor Agents; Zinostatin

This review discusses the development and therapeutic potential of prototype macromolecular drugs for use in cancer chemotherapy, in particular the development and use of SMANCS, a conjugate of neocarzinostatin and poly(styrene-comaleic acid). The various topics covered include a brief description of the chemistry and polymer conjugation, the binding of the conjugate to albumin and the biological behaviour in vitro and in vivo after arterial injection in animals, including plasma half-life, and the lipid solubility of SMANCS in medium chain triglycerides and Lipiodol, a lipid contrast medium suitable for use in X-ray-computed tomography. The biological response-modifying effects and the tumor-targeting mechanism of SMANCS and other macromolecular drugs are also discussed. The latter mechanism is accounted for in terms of a tumor 'enhanced permeability and retention' (or EPR) effect. A principal advantage in the use of SMANCS or other macromolecular drugs is the potential for a reduction or elimination of toxicity. Macromolecular drugs such as a pyran copolymer-NCS conjugate show a marked reduction in bone marrow toxicity normally associated with the use of NCS. This is believed to be due to a hypothetical blood-bone marrow 'barrier' which, relative to NCS, restricts or limits access of the macromolecular drug to the bone marrow. In addition, the clinical possibilities for SMANCS are discussed, including the suggestion that angiotensin II-induced hypertension has clinical potential in improving the selective delivery of macromolecular drugs (i.e. SMANCS) to tumors. Aqueous SMANCS formulations have been tested in pilot studies in patients with solid tumors of the ovary, esophagus, lung, stomach, adrenal gland and in the brain. Formulations based on SMANCS/Lipiodol have been shown to be effective both as a diagnostic tool and for therapeutic use in solid tumors where the formulations are given arterially via a catheter. In a pilot study in primary unresectable hepatoma, an objective reduction in tumor size was observed for about 90% of cases when an adequate amount of the macromolecular drug was administered. A patient receiving such treatment with no active liver cirrhosis and tumor nodules/lesion confined within one liver segment might expect to have a 90% chance of survival after treatment for at least 5 years.

Topics: Animals; Antineoplastic Agents; Humans; Maleic Anhydrides; Neoplasms; Polymers; Polystyrenes; Zinostatin

Topics: Antineoplastic Agents; Capillary Permeability; Carcinoma, Hepatocellular; Drug Carriers; Humans; Iodized Oil; Liver Neoplasms; Maleic Anhydrides; Neoplasms; Polystyrenes; Zinostatin

Three modes of receptor-mediated cancer therapy were reviewed presenting our own data. Employment of tumoricidal cytokines (IFN, TNF, LT) to this type of therapy has been expected to be the most promising approach. However, preclinical and clinical results so far obtained, revealed that they were useful only for the very limited diseases including renal cancer or some hematological malignancies. Second approach is to utilize growth factors conjugated with toxin or carzinostatin which are readily internalized into tumor cells. In this context, transferrin-neocarzinostatin was examined in our laboratory both in vitro and in vivo for its anticancer activity and was found to suppress tumor growth more significantly than neocarzinostatin alone on the basis of molar ratio. Thus this approach may be worthy to be clinically investigated. Adoptive therapy of lymphokine activated killer (LAK) or tumor infiltrating lymphocyte (TIL) may also be categorized into receptor mediated cancer treatment since both are activated by signals through IL-2 receptor. Although clinical evaluation is still on going, the therapy appears to be effective only when effector cells are administered locally to tumors.

Topics: Humans; Immunization, Passive; Immunotoxins; Interferons; Killer Cells, Lymphokine-Activated; Lymphotoxin-alpha; Neoplasms; Transferrin; Tumor Necrosis Factor-alpha; Zinostatin

Highly specific anti-human colorectal carcinoma monoclonal antibody(A7) was developed by fusion of mouse myeloma cells with mouse spleen cells immunized by colon cancer cells. Neocarzinostatin (NCS) was bound to A7 preserving both antibody and drug activities. This conjugate (A7-NCS) was applied for clinical trial. No serious side effects were reported, and half of the eight patients with metastatic liver tumor responded to A7-NCS well. To overcome the variety in the expression of tumor-specific antigen on tumor cells, new types of conjugates were developed. Mitomycin C(MMC) was bound to Dextran sulphate. And this conjugate (M MC-Dex) was bound to A7 with the expectation that MMC would release from Dextran that was delivered to the surface of the cancer cells. This type of conjugate would be effective not only against cancer cells that express antigens detected by A7 but also against any cells around cancer cells detected by A7. The possibility and problems in cancer therapy using immunotoxin are discussed.

Topics: Antibodies, Monoclonal; Dextran Sulfate; Dextrans; Humans; Immunotoxins; In Vitro Techniques; Mitomycin; Mitomycins; Neoplasms; Zinostatin

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biological Availability; Drug Carriers; Humans; Immunoglobulins; Macromolecular Substances; Maleic Anhydrides; Neoplasms; Polystyrenes; Zinostatin

Topics: Animals; Antibiotics, Antineoplastic; Drug Carriers; Endocytosis; Humans; Mice; Neoplasms; Receptors, Transferrin; Transferrin; Zinostatin

Cellular glutathione (GSH) levels were found to be 7-fold higher in a human lung adenocarcinoma cell line (A549) than in a normal human lung fibroblast line (CCL-210). Differential modulation of cellular GSH was explored in these cell lines by (a) stimulation of GSH synthesis by oxothiazolidine-4-carboxylate (OTZ) and (b) inhibition of GSH synthesis by buthionine sulfoximine (BSO). In the tumor cell line, OTZ treatment had no effect; however, GSH levels of 140-170% of control were achieved in the normal fibroblast line. With BSO, the normal cell line was depleted of GSH at a faster relative rate than with the tumor line. Within 7 h, 5% GSH remained in the CCL-210 line while approximately 40% GSH remained in the A549 line. Survival response of normal versus tumor cell lines to selected chemotherapy drugs was compared following modulation of GSH levels. OTZ pretreatment of the A549 line provided no protection to a 1-h exposure to melphalan, cisplatin, or bleomycin; however, OTZ pretreatment of CCL-210 elevated GSH and provided protection to melphalan, cisplatin, and bleomycin (protection ratios at 5% survival of 1.2, 1.4, and 1.4, respectively). Neocarzinostatin toxicity in the normal CCL-210 line pretreated with BSO was greatly reduced (protection ratio at 50% survival = 5.0). The same BSO treatment to A549 cells (40% GSH remaining) yielded a similar survival curve to control cells. These studies demonstrate that selective differential chemotherapy responses of normal versus tumor cells is possible by manipulating the GSH synthetic cycle. Should basic phenotypic differences with regard to reductive capacity exist in vivo, such manipulation in GSH levels might yield a therapeutic gain for carefully selected chemotherapy drugs.

Topics: Antineoplastic Agents; Bleomycin; Buthionine Sulfoximine; Cell Survival; Cells, Cultured; Cisplatin; Glutathione; Humans; Lung; Lung Neoplasms; Melphalan; Methionine Sulfoximine; Neoplasms; Pyrrolidonecarboxylic Acid; Thiazoles; Thiazolidines; Zinostatin

Theoretical considerations for tumor-selective chemotherapy are described which based on the unique character of the tumor neovasculature. Namely, most solid tumors possess four different unique features: hypervasculature, enhanced permeability even to macromolecules, architectural differences, and lack of the lymphatic recovery system. Lipid or lipid contrast medium and macromolecular anticancer agents using prototype drug smancs can be utilized for cancer-selective targeting based on the above four features. Selective targeting with lipid contrast medium with smancs has offered two clinical benefits; definite and pronounced antitumor effect and diagnostic value. These effects can be primarily attributed to the tumor-selective accumulation of the agent, i.e., more than 1,000 times greater in the tumor than in the plasma. As a consequence very few side effects are observed clinically. Primary or secondary hepatoma and lung cancer showed size reduction in more than 90 % of treated patients. Very few side effects such as hematosuppression or inhibited liver function were observed in these cases. Prolongation of life-span was marked in the patients. The above results indicate a new future direction for the development of the tumor-selective chemotherapy.

Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Agents; Biological Availability; Capillary Permeability; Furans; Iodized Oil; Liver Neoplasms; Lung Neoplasms; Macromolecular Substances; Maleic Anhydrides; Mitomycin; Mitomycins; Neoplasms; Neoplasms, Experimental; Polystyrenes; Rabbits; Zinostatin

Selective deposition of lipiodol in primary and metastatic liver cancer, lung cancer, gallbladder cancer, pancreatic cancer and renal cancer was elucidated by plain X-ray film and CT. Selective delivery of anticancer agent, SMANCS was also proved by measurement of its biological activities of removed specimen. Because of these selective delivery of anticancer agent and embolization of neovasculature in the tumor, highly effective chemotherapy of unresectable cancer was established. Drug was given via celiac, the hepatic, bronchial or renal artery mostly 1-5 mg in 1-5 ml of lipiodol once every 3-8 weeks. Antitumor effects of this therapy for hepatocellular carcinoma was confirmed based on decrease in AFP levels (92% of the cases), reduction in tumor size (90% of the cases) and histology. In 76 percent of the patients with the other malignant solid tumors reduction in tumor size was recognized. Decrease in CEA level occurred in 88 percent of the cases with metastatic liver cancer and lung cancer. Major side effect was transient fever in about 50% of cases. Mitomycin C and aclarubicin dissolved in lipiodol showed remarkable antitumor effects for experimental liver cancer.

Topics: Aclarubicin; Animals; Antibiotics, Antineoplastic; Furans; Humans; Infusions, Intra-Arterial; Iodized Oil; Maleic Anhydrides; Mitomycin; Mitomycins; Naphthacenes; Neoplasms; Polystyrenes; Rabbits; Zinostatin

The clinical pharmacology of the anticancer polypeptide neocarzinostatin was studied in 16 patients with disseminated neoplasia using a radioimmunoassay technique. Patients who received 2,400-3,600 U of the drug per square meter BSA by rapid IV infusion had triphasic plasma decay curves. For eight patients with normal hepatic and renal function, neocarzinostatin mean plasma half-lives were 0.14, 0.50, and 7.7 h. The mean plasma drug clearance was 32.4 ml/min/m2 and the apparent volume of distribution 19.3 l/m2. Two patients with liver dysfunction had shorter terminal plasma half-lives and greater drug clearance, while two with renal disease exhibited prolonged plasma half-lives and reduced drug clearances. The mean cumulative urinary excretion of neocarzinostatin was 69.1% of the administered dose at 72 h in three patients with normal hepatic and renal function. One patient with liver disease excreted 90.4%, while a patient with renal disease excreted only 58.1% of the dose in 24 h. In one patient with marked liver disease, biliary excretion accounted for 0.1% of the administered dose in 72 h. Cerebrospinal fluid concentrations of neocarzinostatin studied in two patients showed a CSF penetration of about 16% the plasma concentration at 1-5 h; concentrations persisted for 19 h in one patient with an Omayha reservoir. Neocarzinostatin was rapidly cleared from the plasma and eliminated in the urine. Dosage reductions of 50% are recommended for patients with impaired renal function, while no reduction or escalated doses could be tolerated by patients with liver disease. The pharmacologic data suggest a continuous IV infusion may be a more toxic but perhaps more effective schedule of administration.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Dose-Response Relationship, Drug; Drug Evaluation; Female; Half-Life; Humans; Kinetics; Male; Middle Aged; Neoplasms; Radioimmunoassay; Tissue Distribution; Zinostatin

Topics: Antibiotics, Antineoplastic; Humans; Kinetics; Neoplasms; Radioimmunoassay; Time Factors; Zinostatin

Neocarzinostatin, a polypeptide antibiotic, was administered by both continuous and intermittent intravenous infusion to 76 patients with a variety of malignant diseases. Doses ranged from 500 to 6500 units/m2 X 5 days. With levels greater than or equal to 1800 units/m2, bone marrow suppression (particularly thrombocytopenia) was the dose-limiting toxicity. Delayed bone marrow recovery was less dose-dependent and occurred in 58% of initial treatment courses in solid tumor patients. Allergic reactions were more frequent with intermittent than with continuous infusions (20% vs. 2% of courses). No complete or partial remissions were observed among solid tumor patients although clinical improvement was noted in one patient with mycosis fungoides and one patient with multiple myeloma. One complete and two partial remissions were noted among 21 patients with acute leukemia. There was one complete remission in a patient with chronic leukemia. Leukemic patients on intermittent therapy evidenced greater change in bone marrow cellularity than those treated by continuous infusion. Although neocarzinostatin has some activity in the treatment of acute leukemia, continuous infusion offers no advantage over intermittent therapy.

Topics: Antibiotics, Antineoplastic; Bone Marrow; Drug Administration Schedule; Drug Evaluation; Drug Hypersensitivity; Female; Humans; Infusions, Parenteral; Leukemia; Neoplasms; Zinostatin

An effective treatment schedule with bleomycin in combination with mitomycin and a new effective area in treatment with neocarzinostatin was introduced. Studies on more useful derivatives or analogues of bleomycin and anthracycline antitumor antibiotics were described. Bleomycin PEP thus selected may become a useful agent. Aclacinomycin and various other anthracycline glycosides were isolated from beer fermentation and tested. Future progress in microbiol secondary metabolites useful in cancer treatment was discussed.

Topics: Aclarubicin; Animals; Anthraquinones; Antibiotics, Antineoplastic; Bleomycin; Daunorubicin; DNA; Glycosides; Humans; Neoplasms; Structure-Activity Relationship; Zinostatin

Topics: Antibiotics, Antineoplastic; Humans; Kinetics; Neoplasms; Time Factors; United States; Zinostatin

Neocarzinostatin (NCZ), an acidic polypeptide antibiotic, was given to 47 patients with cancer and leukemia, and tolerance to two schedules, a single dose given as a 2 hour infusion and a continuous infusion over 5 days was investigated. Immediate reactions, including fever, chills, rigor, hypertension and mental confusion, were dose-limiting for the 2 hour infusion schedule, occurring at 3000 U/m2 and higher. Continuous administration for 5 days eliminated the immediate reactions and then hematological toxicity--often prolonged leukopenia and thrombocytopenia--became dose-limiting. Other toxicities of NCZ at both dose schedules included anemia, fever and chills, anorexia, nausea and vomiting, hepatic dysfunction, azotemia, hypophosphatemia, aminoaciduria, stomatitis, phlebitis and/or cellulitis at the venous infusion site and pruritus. Patients with solid tumors who had received little or no prior chemotherapy and had good bone marrow reserve tolerated up to 6000 U/m2/24 hours X 5 days. One patient with previously treated acute myelocytic leukemia was induced into a good partial remission lasting 10 weeks.

Topics: Adolescent; Adult; Aged; Antibiotics, Antineoplastic; Bone Marrow; Child; Drug Administration Schedule; Drug Evaluation; Drug Tolerance; Female; Fever; Humans; Hyperbilirubinemia; Infusions, Parenteral; Leukemia; Leukemia, Myeloid, Acute; Male; Middle Aged; Neoplasms; Remission, Spontaneous; Uremia; Zinostatin

The injection of clinical doses of neocarzinostatin (NCS) in guinea pigs did not result in antibody formation as judged by immunoelectrosyneresis, micro-Ouchterlony agar diffusion, fluorescence polarization, and passive cutaneous anaphylaxis reaction. This confirmed previous work on passive hemagglutination and passive cutaneous anaphylaxis reaction in a heterocytotropic system in guinea pigs. Forty-eight serum samples from 28 patients who were previously treated with NCS alone (8--161 mg) for a period of 8-85 days did not show any sign of antibody formation as revealed by immunoelectrosyneresis, micro-Ouchterlony agar diffusion, and fluorescence polarization techniques. In a homocytotropic system, the passive cutaneous anaphylaxis reaction was carried out with sera of sensitized guinea pigs and test guinea pigs which revealed that no IgE and IgA antibody to NCS was present in the sensitized sera. Those patients with bladder cancer who did not respond to NCS therapy or exhibit any side effects even after 21 mg were found to have proteolytic activity in their sera which degraded NCS very rapidly as revealed by the fluorescence polarization technique.

Topics: Anaphylaxis; Animals; Antibiotics, Antineoplastic; Antibody Formation; Antigens; Guinea Pigs; Humans; Male; Neoplasms; Peptide Hydrolases; Skin Tests; Zinostatin

Twenty-three children with advanced cancer refractory to conventional therapy received weekly iv doses of neocarzinostatin for 5 weeks. Doses were escalated from 500 to 6750 units/m2/week. Four types of toxic manifestations occurred: acute reactions consisting of shaking chills with or without fever and cyanosis (rigor), hypersensitivity, vomiting, and marrow depression. Evidence of oncolytic activity was limited to patients with acute leukemia in whom phase II trials at doses between 3000 and 4500 units/m2 appear warranted.

Topics: Adolescent; Adult; Antibiotics, Antineoplastic; Bone Marrow; Child; Child, Preschool; Drug Evaluation; Drug Hypersensitivity; Humans; Infant; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Neoplasms; Remission, Spontaneous; Shivering; Vomiting; Zinostatin

Neocarzinostatin is a protein antitumor antibiotic isolated from cultures of Streptomyces carzinostaticus var.F41. The drug has undergone extensive clinical trial in Japan, and has been reported active against a variety of human tumors. A phase I and preliminary phase II evaluation of the drug has been performed, using an iv bolus daily x 5 schedule. Ninety-six patients have been treated at doses from 500 to 2250 units/m2/day. Courses were repeated at 4-week intervals if allowed by bone marrow recovery. Dose-limiting toxicity was myelosupppression, which occurred late (median nadir, Day 27). Myelosuppression was more pronounced in patients who had received previous chemotherapy. In nine patients (9%) thrombocytopenia was prolonged (greater than or equal to 45 days) or irreversible. Acute administration of the drug was associated with rigors in approximately half the patients. Gastrointestinal side effects were mild. Three patients had a severe acute reaction resembling anaphylaxis. The maximally tolerated dose for this dose schedule is approximately 2250 units/m2/day. Antitumor activity has been seen in hepatoma and hematologic malignancies. Activity in lung and colorectal carcinoma appears limited with this dose schedule.

Topics: Adolescent; Adult; Aged; Antibiotics, Antineoplastic; Bone Marrow; Carcinoma, Hepatocellular; Child; Drug Evaluation; Female; Humans; Leukemia, Lymphoid; Liver Neoplasms; Male; Middle Aged; Neoplasms; Remission, Spontaneous; Thrombocytopenia; Zinostatin