zinostatin and Urinary-Bladder-Neoplasms

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

Topics: Antibiotics, Antineoplastic; Carcinoma, Transitional Cell; Clinical Trials as Topic; Humans; Male; Middle Aged; Urinary Bladder Neoplasms; Zinostatin

The effects of oxidative stress on double strand DNA breakage were examined in T-24 human bladder tumor cells using various active oxygen producing agents such as hydrogen peroxide (H2O2), bleomycin (BLM), neocarzinostatin (NCS), and x-ray irradiation. Analysis of the DNA by pulsed-field gel electrophoresis (PFGE) revealed that discrete giant DNA fragments of 1-2 Mbp and 200-800 kbp had accumulated in the nuclei of the treated cells. The 1-2 Mbp giant DNA fragments were first observed 2 h after the T-24 cells were exposed to the active oxygen producing agents, or irradiated with x-ray. The appearance and the amounts of 1-2 Mbp and 200-800 kbp giant DNA fragments seemed to depend on the concentration and the type of reagents used or the dose of x-ray. Following the accumulation of giant DNA fragments, another type of DNA fragmentation was detected and DNA fragments smaller than 100 kbp accumulated in the nuclei of the cells irradiated with x-ray or treated with NCS. In addition, DNA ladder formation, which is characteristic of apoptosis, was observed. The giant DNA fragments appeared to arise as a consequence of double-stranded DNA breakage, which occurred earlier than cell lysis, as assessed by 51Cr release. These findings indicate that the formation of giant DNA fragments is a specific characteristic of cells responding to oxidative stress, and it may be an initial event that leads to cell death.

Topics: Bleomycin; Cell Death; Cell Survival; Chromium; DNA Damage; DNA Fragmentation; Electrophoresis, Agar Gel; Electrophoresis, Gel, Pulsed-Field; Humans; Hydrogen Peroxide; Oxidative Stress; Particle Size; Reactive Oxygen Species; Tumor Cells, Cultured; Urinary Bladder Neoplasms; X-Rays; Zinostatin

The cytotoxicity and antitumor effects of zinostatin (NCS) were examined under various conditions of pH using cultured HeLa cells and a transplantable tumor line of WKA rats. The cytotoxicity of NCS against HeLa cells was highly dependent on the pH at ranges of 6-8. When HeLa cells were treated with 0.075 microgram/ml of NCS, the survival rate was about 1% at pH 6.0, while it was near 90% at pH 7.4 and pH 8.0. Even at pH 6.5-6.75, the survival rate was about 50% lower than that seen with pH 7.4 and pH 8.0. The ratio of the dose of NCS for a 90% cell mortality at pH 6.0 to that at pH 7.4 was less than one-seventh. Antitumor effects were assessed by local intra-arterial infusion against tumors 4 or 9 days after inoculation of 10(6) RBT-1 tumor cells into the thigh of rats. When NCS (0.7 mg/kg) in phosphate-buffered saline (PBS) (pH 7.4) or 5 mM lactate (about pH 3.0) was administered, the ratio of average tumor weight about 2 weeks after treatment (tumor weight of the rats given NCS in PBS/tumor weight of the rats given NCS in lactate) was 3.2 or 1.7 for the rats treated 4 or 9 days after tumor inoculation, respectively. Lactate or PBS alone had no effect on the growth of tumor. After treatment there was no difference in body weight change between the group treated with NCS in lactate and the group treated with NCS in PBS. We conclude that the cytotoxicity of NCS was potentiated under acidic conditions, both in vitro and in vivo.

Topics: Animals; Antibiotics, Antineoplastic; Body Weight; Carcinoma, Transitional Cell; Cell Survival; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Synergism; Female; HeLa Cells; Humans; Hydrogen-Ion Concentration; Rats; Rats, Inbred Strains; Urinary Bladder Neoplasms; Zinostatin

Two cases of bladder carcinoma are described. The patients were of similar age, were both smokers and were treated for the same period, but exhibited completely different later clinical courses. Initially, both had a single, papillary, pedunculate tumor, identified as a transitional cell carcinoma, grade 2, pTa. One patient, six years later, had multiple papillary tumors covering almost all the mucosal surface and underwent simple cystectomy. Histologically the tumors were identified as transitional cell carcinomas, grade 2, pT1. The other patient, nine years later, had a single nodular invasive tumor with a concomitant, very tiny papillary tumor and underwent radical cystectomy. Histologically the tumor was transitional cell carcinoma, grade 2 greater than 3, pT4. Many of the questions raised by these cases are unanswered, but comparison of such cases should provide some clues to the natural history of bladder carcinoma.

Topics: Adult; Carcinoma, Transitional Cell; Cystoscopy; Humans; Male; Neoplasm Invasiveness; Neoplasm Recurrence, Local; Smoking; Time Factors; Urinary Bladder Neoplasms; Zinostatin

The effect of instillation therapy using CA alone or in combination with MMC, NCS or CQ was examined in 111 patients (92 males and 19 females, aged 32-87 years old with an average age of 66 years) with multiple superficial bladder tumors. The response rate of 29 patients given CA 400 mg alone was 48.3%, that of 25 patients given combination therapy of CA 200 mg and MMC 20 mg was 84.0%, that of 28 patients given combination therapy of CA 200 mg and NCS 4,000 U was 71.4%, that of 22 patients given combination therapy of CA 200 mg and NCS 6,000 U was 95.5% and that of 7 patients given combination therapy of CA 200 mg and CQ 10 mg was 100%. The response rates of the patients given any of the combination therapies were higher than that of the patients given CA alone. But because MMC, NCS and CQ were not administered singly, combination therapy cannot be concluded to be superior to single therapy. There was little difference between the response rate of primary cases and that of follow up cases. The side effects were all symptoms of local irritation, and were not indicative of systemic damage. Side effects were seen in 3.4%, 71.4%, 40.0% and 3.6% of the patients given CA alone, CA + CQ combination therapy, CA + MMC combination therapy and CA + NCS (4,000) therapy, respectively, combination therapy of CA and CQ producing the highest percentage of side effects.

Topics: Adult; Aged; Carbazilquinone; Cytarabine; Drug Evaluation; Drug Therapy, Combination; Female; Humans; Injections; Male; Middle Aged; Mitomycin; Mitomycins; Urinary Bladder; Urinary Bladder Neoplasms; Zinostatin

Topics: Adult; Aged; Anorexia; Antibiotics, Antineoplastic; Carcinoma, Transitional Cell; Fatigue; Humans; Leukopenia; Male; Middle Aged; Neoplasm Recurrence, Local; Urinary Bladder Neoplasms; Zinostatin

Neocarzinostatin (NCZ), a new antitumor antibiotic, was administered to 19 patients with bladder cancer, 16 patients with prostatic cancer, and 3 patients with hepatoma. All patients had objectively measurable metastatic lesions including 21 with palpable nodes or subcutaneous nodules, 10 with pulmonary nodules as demonstrated by chest x-ray, 4 with malignant hepatomegaly, and 3 with bidimensional pelvic masses as demonstrated by CT scanning. Sixty-five courses of NCZ were administered via an intravenous bolus daily for five days with dosages ranging from 1500 to 3000 U/m2. Immediate toxicity was not dose-limiting except for 1 episode of anaphylaxis and 1 of acute renal failure. Myelotoxicity was delayed, dose-dependent, noncumulative, and dose-limiting. Thrombocytopenia was prolonged or irreversible in 5 cases. The maximally tolerated dose was 2750 U/m2. One patient with NCZ-associated pulmonary fibrosis and 1 with biopsy-proven hepatitis are discussed in detail. Neocarzinostatin demonstrated minimal therapeutic activity (1 partial remission) in patients with bladder cancer. There was no response in patients with prostatic cancer or hepatoma.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Carcinoma, Transitional Cell; Drug Administration Schedule; Drug Evaluation; Female; Hematoma; Humans; Leukopenia; Liver; Male; Middle Aged; Neoplasm Metastasis; Prostatic Neoplasms; Respiratory Function Tests; Thrombocytopenia; Urinary Bladder Neoplasms; Zinostatin

An uptake of fluorescein isothiocyanate labeled neocarzinostatin into normal and cancerous epithelial cells from bladder was investigated. Results showed that neocarzinostatin traversed the cell membrane into cytosol and nuclei, and it appeared to have a preferential cytotoxicity for the cancer cell.

Topics: Antibiotics, Antineoplastic; Biological Transport; Epithelium; Fluoresceins; Humans; Microscopy, Fluorescence; Thiocyanates; Urinary Bladder; Urinary Bladder Neoplasms; Zinostatin

Some aspects of the absorption, distribution, and excretion of neocarzinostatin (NCS), a proteinous antitumor antibiotic, were studied in rabbits. NCS was given intravenously (i.v.) via the auricular vein, or [(14)C]NCS was instilled directly into the cavity of the bladder by tubing. In both groups, ureterostomy was performed, so that the drug excreted in the urine did not pass through the bladder. The results showed extremely rapid renal clearance; namely, two-thirds of the total recovered was excreted in the first 5 min. It was also shown that drug infused into the bladder cavity could be recovered in urine from the ureterostomized ureter. Also, the level of biological activity of NCS in bladder tissues after i.v. administration is significantly lower when ureterostomy is performed. Thus, evidence is presented for the absorption of NCS into bladder tissue from the lumen of the bladder. The high levels of NCS in bladder tissue are due to this effect as well as to accumulation via the iliac artery. These data should encourage further trials of NCS in bladder cancer. A study of urine containing NCS derived from i.v. administration showed an increase in antibacterial activity upon incubation, followed by a decrease. These effects are probably due to proteolysis, as shown by the appearance of a low-molecular-weight fragment and by the absence of such an increase in the presence of inhibitors of proteolysis.

Topics: Animals; Antibiotics, Antineoplastic; Injections, Intravenous; Rabbits; Urinary Bladder; Urinary Bladder Neoplasms; Zinostatin