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Enhanced anticancer efficacy by use of mitomycin C adsorbed on small activated carbon particles in mice.

A new dosage form of mitomycin C (MMC-CH) was tested for toxicity and therapeutic efficacy against intraperitoneally inoculated cancer cells in mice. MMC-CH is a suspension comprising 7.16 mg/ml of activated carbon particles, 1 mg/ml of mitomycin C (MMC) and 20 mg/ml of polyvinylpyrrolidone in saline. The LD50 value determined by means of the Litchfield-Wilcoxon method after intraperitoneal administration was 2.29 times higher for MMC-CH than for MMC aqueous solution. Mice were inoculated intraperitoneally with 2 X 10(5) P388 leukemia cells and given an intraperitoneal injection of 10 to 1.25 mg/kg of MMC in the form of MMC-CH or MMC aqueous solution 24 hr after the inoculation. The median survival time was prolonged to 270.5%, 223.0% or 168.3% by MMC-CH at the dose equivalent to 10, 5 or 2.5 mg/kg of MMC, respectively, while it was prolonged to 182.7%, 139.6% or 155.4% by MMC aqueous solution at the dose of 5, 2.5 or 1.25 mg/kg of MMC, respectively, as compared with the median survival time in the non-treated group. MMC-CH prolonged the survival time to more than 120% as compared with the same dose of MMC given as MMC aqueous solution, and was less toxic.

Adsorption↗

Influence of caffeine on mitomycin C induced mutagenesis: a simple explanation.

It has recently been suggested that caffeine probably represses mutations induced by mitomycin C by selectively killing cells with damaged DNA resulting from inhibition of an error-prone repair process which fails to be completed. A more likely explanation is that caffeine exerts its inhibitory effects on mitomycin C mutagenesis because of its well-documented ability to inhibit urvA.B.C-dependent excision repair.

Caffeine↗

[The induction of sister chromatid exchange by diethylstilbestrol and mitomycin C in lymphocytes of mothers and their newborn infants].

Lymphocytes of mothers and their newborn infants were treated with varying concentrations of diethylstilbestrol (10(-6) M, 10(-5) M and 10(-4) M) and mitomycin C (0.003, 0.009 and 0.03 microgram/ml), and the incidence of sister chromatid exchanges (SCE) was determined. The results showed that the spontaneous SCE rate in the newborns is less than that of their mothers. A dose-related increase in SCEs was observed in cells exposed to the alkylating chemical mitomycin C, while increases in SCEs were not noted in cultures exposed to diethylstilbestrol. No different susceptibilities of lymphocytes from mothers and newborns to the chemical induction were observed.

Diethylstilbestrol↗

[A case of gastric cancer with marked response to intra-arterial infusion of cisplatinum, mitomycin C and 5-fluorouracil].

The prognosis for patients with unresectable gastric cancer is so poor that 50% survival time is no more than 3 months. A 58-year-old woman was admitted for advanced gastric cancer with multiple liver metastases. Preoperatively, she received hepatic arterial infusion of 75 mg/m2 of cis-platinum during abdominal angiography. As laparotomy revealed an unresectable gastric tumor of the classification H3P2N4S3, a catheter was introduced into the aorta at the level of the celiac axis via a branch of the right femoral artery and 10 mg of Mitomycin C was infused into the abdominal aorta through the catheter. Postoperative chemotherapy consisted of continuous intra-arterial infusion of 250 mg/day of 5-Fluorouracil for 14 days, followed by infusion of another 10 mg of Mitomycin C. Daily oral administration of 600 mg of tegafur was continued in the outpatient clinic. Three months after surgery, the primary and hepatic metastatic lesions had regressed by 76 and 88-98% on abdominal computed tomography and gastric fluoroscopy, respectively. The dimensions of the lesions remained unchanged for the subsequent two months, and their responses to the treatment were judged PR. Eight months after surgery, the patient is in good general condition.

Antineoplastic Combined Chemotherapy Protocols↗

Treatment schedule of intravesical chemotherapy with mitomycin C in superficial bladder cancer: short-term courses or maintenance therapy.

Intravesical chemotherapy using mitomycin C in patients with superficial bladder cancer after transurethral resection (TUR) has proved to be highly effective in preventing tumor recurrences and/or progression. No consensus has been reached on the appropriate dose and treatment schedule. This and other variable factors such as different criteria for entry and follow-up in the reported studies so far make it impossible to compare the results. There are indications that long-term mitomycin C instillation therapy improves recurrence rate, progression rate, and survival. Considering prognostic factors in patients with superficial bladder tumors, it is justified and necessary to investigate this regimen in future protocols.

Administration, Intravesical↗

Compositional stability of artificial heterogeneous tumors in vivo: use of mitomycin C as a cytotoxic probe.

A major part of the overall response of solid cancers to cytotoxic treatments will be due to the differential sensitivities of the neoplastic cell subpopulations present. To quantitatively investigate this, artificial heterogeneous human colon xenograft tumors were constructed using two clonally related cell lines (A and D) which were mixed to create compositions of approximately 9:1 or 1:9 A:D cells. Then, the pure A, D, or admixed tumors were challenged with mitomycin C which kills A cells more efficiently than D cells by a factor of about 2.3 as determined by in vitro survival curve inactivation slopes. This difference was also exhibited in vivo by the post-mitomycin C cell survival responses determined by excision assay and by the shapes of the regrowth curves of the pure A and D or admixed tumors. By approximately 30 days after treatment, artificial heterogeneous tumors had reached a new stable cellular composition which could be quantitatively predicted based on the individual survival of A and D cells from pure clonal tumors measured 24 h after treatment. Thus, in this model system, cytotoxic treatment of heterogeneous neoplasms produced predictable and stable, albeit altered, percentage admixtures of subpopulations. This result is consistent with the observed decreased clinical responsivity of primary tumors to sequential courses of therapy due to selection of preexisting resistant subpopulations.

Animals↗

[Effect of a calcium influx blocker, verapamil, on the sensitivity of human bladder cancer cells to adriamycin and mitomycin C].

We have investigated the effect of verapamil on the cytotoxicity of adriamycin and mitomycin C with human bladder cancer cell lines T-24 and JTC-30. The concentration of verapamil was 10 M, and adriamycin and mitomycin C were used at the concentrations ranging from 10(-2) micrograms/ml to 10 micrograms/ml. The efficacy of drugs were evaluated using cytotoxicity and colony forming assays. Judging from the results of these assays, no significant difference was observed between the drugs in combination with verapamil and drugs alone. The results indicate verapamil has no enhancement for the cytotoxic activity of the anticancer drugs when cell lines T-24 and JTC-30 are used.

Doxorubicin↗

Extensive non-small cell lung cancer treated with mitomycin, cisplatin, and vindesine (MiPE): a Southwest Oncology Group Study.

Ninety-seven previously untreated patients with metastatic non-small cell lung cancer were treated with combination chemotherapy consisting of mitomycin (10 mg/m2) on Day 1, cisplatin (50 mg/m2) on Days 1 and 22, and vindesine (3 mg/m2) on Days 1 and 22 (MiPE). MiPE was repeated at 6-week intervals until disease progression or unacceptable toxicity. The overall response rate was 33%. There were seven complete responses (7%) and 25 partial responses (26%). The median progression-free interval for responding patients was 7 months. Median survival for all patients was 5 months, with 16% surviving 1 year. One patient died from sepsis while neutropenic. The results with MiPE treatment for patients with non-small cell lung cancer compare favorably to other mitomycin-vinca combinations previously tested in the Southwest Oncology Group.

Aged↗

Chemotherapy of advanced gastric cancer: a study of 43 consecutive cases treated with fluorouracil, adriamycin and mitomycin C (FAM).

All consecutive patients with advanced gastric carcinoma who came to the Oncology Dept. of the "L. Pierantoni Hospital" in Forlì, between June 1, 1980 and August 30, 1983, were treated with 5-fluorouracil, adriamycin and mitomycin C (FAM). None of the patients had previously received chemotherapy. The dominant location of metastasis was the liver in 21 pts (48.8%), the abdomen in 15 pts (34.8%) and distant organs in 7 pts (16.2%). The schedule of FAM regimen used was: 5 Fluorouracil, 600 mg/m2, days 1, 8, 29, 36; Mitomycin C 10, mg/m2, day 1; Adriamycin, 30 mg/m2, days 1, 29. Complete remission (CR) was reached in 2 pts (4.6%) with a median length of response (m.l.r.) of 55 weeks (range 20-90), partial remission (PR) in 9 pts (20.9%) with a m.l.r. of 15.1 weeks (2.2-60), no change (N.C.) in 19 pts (44%) with a m.l.r. of 10 weeks (2.2-54) and progression (P) in 13 pts (30.2%). Median survival of patients in CR + PR considered together was 48 weeks (12 months), for the NC pts 20 weeks (5 months) and for those in P 14.1 weeks (3.5 months). The authors reached the conclusion that gastric carcinoma may be treated with FAM both for palliation and to improve survival even if in a small number of patients.

Adult↗

The influence of family history of cancer, irradiation and anticancer medication (mitomycin C), on the occurrence of multiple primary neoplasms with breast cancer--statistical analysis by the person-year method.

The influence of family history of cancer, radiation therapy and anticancer drug therapy (mitomycin C) on the occurrence of multiple primary neoplasms, following treatment of a first primary cancer of the breast, was analyzed by the person-year method in 1,359 patients, in Japan. During 14,371.8 person-years of observation, 111 multiple primary neoplasms including bilateral breast cancers were found in 109 patients. The incidence rate of multiple primary neoplasms were 0.00772 per person-year. The incidence in patients with a family history of cancer was 1.29 times greater than that in patients without such a family history, and the incidence in patients with a family history of breast cancer was about three times greater than that in those without it (p less than 0.01). Radiation therapy raised the occurrence of subsequent primary neoplasms 1.28-fold (or 1.62 fold after 5 years), and mitomycin C (a total dose of 0.8 mg/kg) therapy caused no increase in the occurrence of subsequent primary cancers, after an observation of 10 years or so.

Adult↗

[Sequential intravesical chemotherapy with mitomycin C and adriamycin for superficial bladder tumor (preliminary report)].

Intravesical chemotherapy with sequential instillation of mitomycin C and adriamycin was carried out on 19 patients with superficial bladder cancer (Ta, T1 and Tis). Twenty milligram of mitomycin C on day 1 and 40 mg of adriamycin on day 2 were instilled into the bladder, this treatment being repeated weekly for 5 consecutive weeks if there were no serious side effects. The following results were obtained. Of 16 evaluable patients, 10 patients (63%) achieved complete response and 2 patients achieved partial response, 4 patients showing no response. In patients with high grade tumor, especially with carcinoma in situ, a high CR rate (6/7 or 86%) was achieved. Chemical cystitis occurred in 10 out of 19 (53%) patients. In 5 of the 6 patients who suffered from severe cystitis symptoms, treatment was discontinued. However, the symptoms resolved within 4 weeks in all patients.

Adult↗

Phase II study of 7-N-(p-hydroxyphenyl)-mitomycin C (KW2083) in patients with advanced non-small cell carcinoma of the lung and metastatic pulmonary tumors.

Twenty-six patients with non-small cell carcinoma of the lung and 25 with metastatic pulmonary tumors were treated by intravenous injection of 7-N-(p-hydroxyphenyl)-mitomycin C (KW2083), a derivative of mitomycin C, either at a single 70-mg/m2 dose or at a dose of 20-30 mg/m2 once a week for 3 weeks. Two patients with adenocarcinoma among 21 evaluable patients with non-small cell carcinoma of the lung, and one with embryonal cell carcinoma among 21 patients with metastatic pulmonary tumors achieved partial response lasting 5 to 7 weeks. In these three patients, KW2083 was administered by a single 70-mg/m2 dose, and no patients who received a dose of 20-30 mg/m2 weekly achieved objective response. Myelosuppression, primarily thrombocytopenia, was pronounced with either treatment regimen and it was the major dose-limiting toxicity.

Adult↗

Importance of Fe2+-ADP and the relative unimportance of OH in the mechanism of mitomycin C-induced lipid peroxidation.

The mechanism of mitomycin C-induced lipid peroxidation has been studied at pH 7.5, using systems containing phospholipid membranes (liposomes) and an Fe3+-ADP complex with purified NADPH-cytochrome P-450 reductase. Both O2- and H2O2 are generated during the aerobic enzyme-catalyzed reaction in the presence of mitomycin C. Hydroxyl radical is formed in the reaction by the reduction of H2O2. This is catalyzed by the Fe2+-ADP complex in a phosphate buffer or to a lesser extent when in a Tris-HCl buffer. The reduction of Fe3+-ADP to Fe2+-ADP is mainly achieved by O2-. The resulting Fe2+-ADP in the presence of O2 forms a perferryl ion complex which is a powerful stimulator of lipid peroxidation. However, the formation of such an iron-oxygen complex is strongly inhibited by phosphate ions, which do not interfere with the generation of OH radicals. These findings suggest that, since lipid peroxidation occurs in a Tris-HCl buffer (but not in a phosphate buffer), the OH radical is unlikely to be involved in the observed lipid peroxidation process.

Adenosine Diphosphate↗

Bleomycin-mitomycin C in advanced squamous cell carcinoma of the female genital tract.

Bleomycin and mitomycin C have been reported to be active against advanced squamous cell carcinoma of the uterine cervix. Miyamoto et al reported a total response rate of 93% and complete response in 80% of the first 15 patients treated by sequential combination of bleomycin and mitomycin C. Updated results by Miyamoto reveal an 88.3% total response rate with a 65.3% complete response. However, others have reported poor results using the protocol outlined by Miyamoto. Using this protocol, 11 patients with advanced squamous cell carcinoma were treated at the authors' institution. There were no complete responses: one patient with partial response (9%), four with stable disease (36%), and six (55%) with progressive disease.

Adult↗

Enhanced lymphatic delivery of mitomycin C conjugated with dextran.

Absorption and lymphatic transfer of a polymeric prodrug of mitomycin C (MMC), mitomycin C-dextran conjugate (MMC-D), following i.m. injection were studied in rats in order to assess the feasibility of a macromolecular prodrug as a lymphotropic delivery system. Three types of MMC-D, conjugates with dextran with molecular weights of 10,000, 70,000 and 500,000, were synthesized, and the disposition of MMC was determined by bioassay. Following i.m. injection of MMC-D, MMC was retained at the injection site for a long period in a conjugated form while MMC administered as a free form disappeared rapidly. The disappearance was markedly influenced by the size of carrier dextran, because the remaining amount of MMC increased with an increase of molecular size. The lymphatic uptake of the drug was evaluated by determining the concentration in the regional lymph nodes and thoracic lymph fluid. In contrast to a slight lymphatic uptake following i.v. and i.m. injection of free MMC, MMC-D exhibited remarkable accumulation in the regional lymph nodes after i.m. injection which persisted up to 48 hr. MMC-D (Mr 10,000) appeared in the thoracic lymph as both the conjugated and the free form. Larger MMC-D gave a persistent supply of free MMC in thoracic lymph, suggesting that it was accumulated in the lymph node and supplying MMC continuously. These MMC-Ds suppressed the lymph node metastases introduced by a s.c. inoculation of L1210 leukemia cells. The usefulness of MMC-D as a lymphotropic delivery system for preventing lymphatic metastasis of cancer was suggested.

Animals↗

A phase I-II study of continuous 5-day infusion mitomycin-C.

A phase I-II study was undertaken to establish the maximum-tolerated dose of a continuous 5-day infusion of mitomycin-C and its efficacy in patients with advanced metastatic drug-resistant breast and gastrointestinal malignancies. The dose-limiting toxicity was myelosuppression, predominantly thrombocytopenia, and was severe and cumulative. Nonhematologic toxicity was infrequent, and no renal or cardiac toxicity was seen. For patients with breast cancer who had received extensive prior therapy, 3 mg/m2/day for 5 days repeated every 6-8 weeks were well-tolerated doses; and for patients with gastrointestinal cancer, the maximum-tolerated dose was 4 mg/m2/day. One patient with breast cancer had a partial response lasting 4 months, and no responses were observed in patients with gastrointestinal cancer. The administration of mitomycin-C by continuous infusion did not appear to have improved its therapeutic index.

Aged↗

[Mitomycin C: current status of knowledge and use in laryngeal tumors].

The Mitomycin are a family of antibiotics useful in the treatment of breast, lung, stomach, colorectal and other solid tumours. One member of the family, MC (Mitomycin C) is examined and the present biochemical, physiological, microbiological, pharmacological and clinical knowledge of the drug and its use in laryngeal tumours is reviewed.

Clinical Trials as Topic↗

[Stage P-1 primary neoplasia of the bladder. Critical evaluation of results obtained with the use of adriamycin and mitomycin C in the prevention of recurrences].

However adequately treated, surface carcinomas of the bladder recur sooner or later with infiltration found in about 10% of cases. Any development that may offer therapeutic progress and reduce the incidence of recurrences is therefore of primary importance. Two homogeneous groups of patients were selected for the present study: 35 were given Adriamycin and 25 Mitomycin C. In evaluating results, the incidence of recurrences in relation to the primary neoplasia and the existence of single or multiple tumors was analysed. It is concluded that Mitomycin C in association with either T.U.R. or T.V.R. is a particularly useful and indubitably effective form of topical chemotherapy in cases of single or multiple primary neoplasias.

Administration, Topical↗