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PubMed1998

The importance of DT-diaphorase in mitomycin C resistance in human colon cancer cell lines.

BACKGROUND: Prior studies have suggested the multifactorial nature of mitomycin C (MMC) resistance. However, the relative importance of the different resistance mechanisms is unknown. MATERIALS AND METHODS: A panel of colon cancer cell lines with levels of MMC resistance from 2- to 15-fold compared to the parent line HT-29 was produced by repeated MMC exposure. Cell survival was measured using clonogenic assay. Glutathione and related enzymes and DT-diaphorase were measured using biochemical assays. P-glycoprotein expression was measured using flow cytometry. Topoisomerase II activity was measured using the pBR322 DNA relaxation assay. RESULTS: Multiple drug resistance mechanisms were altered in the resistant cell lines (glutathione reductase, glutathione peroxidase, topoisomerase II). However, the level of DT-diaphorase correlated best with the degree of MMC resistance. The importance of DT-diaphorase was confirmed by using BMY 25282, an MMC analogue which is less dependent on DT-diaphorase for activation. Resistance in the HT-29R54 cell line was 15-fold with MMC compared to 5-fold with BMY 25282. P-glycoprotein-mediated resistance does not appear important in this model. CONCLUSIONS: Although MMC resistance appears to be multifactorial, the results of this study strongly suggest that DT-diaphorase is the major contributor to MMC resistance under aerobic conditions. Strategies to enhance drug activation may therefore be useful for reversing MMC resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1991

Phase II study of intra-arterial fluorouracil and mitomycin-C for liver metastases of colorectal cancer.

Effectiveness, toxicity and complications of 5-fluorouracil (FU) and mitomycin-C (MMC) treatment were analyzed in 30 patients with metastatic colorectal cancer confined to the liver. The treatment schedule was FU 2.0-2.5 g/day for 5 days followed by MMC 10 mg/m2 every 2 h on day 6 to a maximum total dose of 60 mg. Treatment courses were repeated every 6 weeks and were given on an outpatient basis via external pump and arterial port systems. In 30 fully evaluable patients, one complete response, 17 partial responses (overall response rate 60%), and stabilization of disease in 8 patients (26%) were obtained for a median duration of 13 months. Median overall survival was 18.2 months (25.5 months for responding patients, 15 months for nonresponders). Grade 1-2 toxicity (WHO classification) consisted of leukopenia (23%), mucositis (20%), nausea/vomiting (16%), and abdominal pain (10%). Two patients (7%) developed severe mucositis. No life-threatening side effects were observed; in particular, there was no sclerosing cholangitis or chemical hepatitis. Catheter-related problems (occlusion, displacement, rupture, infection) occurred in 10 patients (33%) at a median follow-up time of 12 months. We conclude that intra-arterial FU and MMC constitute an effective, safe, and nontoxic treatment in metastatic colorectal cancer confined to the liver. Catheter-related problems are the most important factors limiting treatment.

Adult↗
PubMed1984

Phase I study of 7-N-(p-hydroxyphenyl)-mitomycin C.

The Phase I study of N-7-(p-hydroxyphenyl)-mitomycin C (KW 2083, M 83) was performed. The dose-limiting toxicity was leukopenia and thrombocytopenia and a maximum tolerable dose was 70 mg/m2. Nonhematologic toxicities included nausea (44%), vomiting (13%), diarrhea (2.7%), azotemia (8.1%), proteinuria (5.4%), alopecia (8.1%) and elevated hepatic enzymes (2.7%). This Phase I study indicates that the recommended starting dose for Phase II studies for patients without significant myelosuppression would be 50 mg/m2 at 6 week intervals in an intravenous push. KW 2083 should be avoided in patients with impaired renal functions and proteinuria because of permanent renal damages caused by the drug.

Aged↗
PubMed1985

Phase II study of vincristine, mitomycin-C and mitoxantrone in advanced breast cancer: a preliminary report of response and toxicity.

Nineteen patients with advanced, previously treated breast cancer received treatment with vincristine 2 mg i.v., mitomycin-C 6 mg/m2 and mitoxantrone (Novantrone; dihydroxyanthracenedione) 12 mg/m2 i.v. every three weeks. Thirteen patients are evaluable for response and toxicity. Partial remission was seen in six patients, with soft tissue, bone and visceral metastases and static disease in a further four patients. Median duration of response has not yet been reached (8+ months). Toxicity was mild and predictable, with no patient experiencing severe nausea and vomiting, and only four of the patients requiring a wig for alopecia. Malaise and lethargy were common in those patients receiving more than three courses, and an increase in the mean corpuscular volume (MCV) together with a fall in haemoglobin were seen in patients receiving multiple courses of treatment. The study suggests that this combination is active, and may prove useful with other agents in the treatment of breast cancer.

Adolescent↗
PubMed1986

Selective in vitro and in vivo growth inhibition against human yolk sac tumor cell lines by purified antibody against human alpha-fetoprotein conjugated with mitomycin C via human serum albumin.

The anticancer drug mitomycin C (MMC) was conjugated with an affinity-purified horse antibody to human alpha-fetoprotein (aAFP) with human serum albumin (HSA) as the intermediate drug carrier. The conjugate (aAFP:HSA:MMC molar ratio, 1:1:30) retained full antibody binding activity as determined by a competitive binding radioimmunoassay. In a cytotoxicity test in which the AFP-producing human yolk sac tumor TG-1 cells were preincubated with test materials for 2 h followed by an additional 48-h culture in fresh medium, the conjugate was 20-fold more cytotoxic than free MMC at an equivalent MMC concentration of 100 ng/ml. The in vivo antitumor effect of the conjugate was tested against the human yolk sac tumor JOG-9 growing in athymic nude mice. When the tumor-bearing mice were treated with a total of 6 injections given on 2 consecutive days and then every other day starting 8 days after SC tumor inoculation [2 (equivalent MMC) microgram/head per injection], the conjugate retarded tumor growth more effectively than free MMC and normal horse immunoglobulin conjugate.

Adolescent↗
PubMed1983

Synergistic anti-tumor effect of mini-cells prepared from Salmonella typhimurium with mitomycin C in EL4-bearing mice.

A statistically significant increase in survival time was observed in EL4-bearing mice after a mini-cell inoculation. However, no case of survival for over 30 days was observed after an EL4 graft in mice treated with mini-cells alone. Fifty percent of the mice survived for 40 days after an EL4 transplantation when the mice were treated with both an IV injection of mini-cells and an SC injection of mitomycin C. The mini-cell injection restored the macrophage chemotaxis activity in EL4-bearing mice but did not restore the lymphocyte activities.

Animals↗
PubMed1987

Augmentation of the generation of cell-mediated cytotoxicity in culture by mitomycin C.

The effects of mitomycin C (MMC) on the generation of cell-mediated cytotoxicity in primary stimulation culture of human peripheral blood mononuclear cells (PBM) with the B lymphoblastoid Raji cell line were assessed. The cell-mediated cytotoxicity induced in culture was significantly augmented when MMC was added to cultures on day -1 to day 3 for 24 h at concentrations of 2.5 X 10(-2) micrograms/ml and 2.5 X 10(-3) micrograms/ml. To identify the cell populations affected by MMC, PBM were separated by adherence to plastic after treatment with MMC for 24 h (day -1). The two populations were recombined with untreated separated cells and stimulated with antigen. The ability to develop an augmented cell-mediated cytotoxicity was associated with the adherent cell fraction of MMC-treated PBM. Therefore, the ability of MMC-treated adherent cells to produce interleukin 1 (IL 1) was examined. Significantly higher levels of IL 1 were produced by treated cells as compared to untreated adherent cells. The results appear to indicate that the selective effects of MMC on the adherent cell fraction, especially the modification of IL 1 production, may be involved in the mechanisms of MMC-induced augmented cell-mediated cytotoxicity.

Cells, Cultured↗
PubMed1987

5-fluorouracil, adriamycin, and mitomycin-C (FAM) chemotherapy in advanced adenocarcinoma of the lung: comparison of two dosage schedules.

Fifty patients with inoperable adenocarcinoma of the lung were randomized in a prospective study to receive either standard doses or high doses of 5-fluorouracil, adriamycin, and mitomycin-C (FAM versus Hi-FAM). The response/stabilization rate was 32% for FAM and 34% for Hi-FAM (P greater than 0.05), and the median survival was 27 weeks for FAM group and 24 weeks for Hi-FAM group (P greater than 0.05). Myelotoxicity was mild in FAM, but moderate to severe in Hi-FAM. It is concluded that Hi-FAM did not yield a higher response rate or median survival compared with FAM, but caused significantly more severe myelotoxicity.

Adenocarcinoma↗
PubMed1982

Treatment of advanced gastric carcinoma with 5-fluorouracil adriamycin, and mitomycin C (FAM).

Thirty-three evaluable patients with advanced gastric adenocarcinoma were treated with a combination of 5-fluorouracil, adriamycin, and mitomycin C (FAM). Two complete and five partial remissions (21% response rate) were observed. The overall median survival of all 33 patients was 5.9 months. Responding patients had significantly better survival than the non-responders (P less than 0.02). Analysis of the results according to sex, pretreatment performance status, and the histologic differentiation of the tumor failed to demonstrate that any of these factors influenced therapeutic results. The low response rate to FAM found in this study might be related to the fact that in the majority of the patients (85%) the primary gastric tumor had not been resected. The side-effects of this regimen were moderate. Taking into account the low response rate and the moderate myelotoxicity observed, a more intensive use of these three drugs in combination is suggested.

Adult↗
PubMed1983

Combination of dacarbazine, mitomycin C, 5-fluorouracil and vincristine in advanced colorectal cancer.

Thirty patients with advanced measurable colorectal cancer received monthly courses of a combination of dacarbazine, mitomycin C, 5-fluorouracil, and vincristine (FIVMit-Or). Four of the patients had received prior chemotherapy. Two patients were not evaluable for response. Objective response was obtained in four patients. Severe toxicity was encountered in 11 patients. It is concluded that unlike the four-drug combination of 5-fluorouracil, DTIC, vincristine and BCNU (FIVB), the present regimen did not have significant antitumour activity in advanced colorectal cancer.

Adult↗
PubMed1988

Pharmacokinetics and toxicity of mitomycin C in rodents, given alone, in combination, or after induction of microsomal drug metabolism.

The pharmacokinetics of mitomycin (MMC) was studied in Wistar rats. Up to five half-lives, the plasma concentration-time curve was biphasic. The AUC changed linearly with increasing doses between 0.5 and 7.5 mg/kg, which corresponds to 0.2 and 3 times the LD50 value in rats. Most of the drug was metabolized, and only 1%-2% and 10%-15% of the dose was eliminated unchanged by biliary and urinary excretion, respectively. The AUC of MMC at the LD50 is slightly less than that reported for the human MTD. Inoculation of MMC together with 5-fluorouracil and doxorubicin did not change the terminal half-life of MMC but decreased the total body clearance and the volume of distribution. The lack of significant influence of phenobarbital and 3-methylcholanthrene pretreatment on the terminal elimination half-life suggests that microsomal drug-metabolizing enzymes inducible by these compounds do not play a decisive role in the in vivo biotransformation of MMC.

Animals↗
PubMed1989

Modulation of the antineoplastic efficacy of mitomycin C by dicoumarol in vivo.

Dicoumarol (DIC) modulates the intracellular metabolism of mitomycin C (MC) in vitro, increasing the toxicity of MC to hypoxic EMT6 cells and decreasing its toxicity to aerobic cells. The present experiments assessed whether DIC could be used to increase the therapeutic ratio attainable in vivo when MC was used as an adjunct to radiotherapy. Experiments with transplanted EMT6 tumors in mice showed that DIC increased the toxicity of MC to hypoxic tumor cells and increased the antineoplastic efficacy of regimens combining MC with radiation. DIC did not increase the hematologic toxicity of MC, and pretreatment with DIC plus MC did not augment radiation-induced skin reactions. The increase in antineoplastic effect was therefore obtained without a concomitant increase in normal tissue toxicities, and therapeutic gain was obtained.

Animals↗
PubMed1987

Sequential instillation therapy with mitomycin C and adriamycin for superficial bladder tumors.

From October 1983 to September 1985, 84 patients with superficial bladder tumor (Ta, Tl, Tis) were treated with sequential instillation of mitomycin C (MMC) and adriamycin (ADM). Doses of 20 mg MMC on day 1 and 40 mg ADM on day 2 were instilled into the bladder and retained for at least 2 h; this was repeated once a week for 5 consecutive weeks. Patients who achieved complete response (CR), were randomized and underwent prophylactic treatment taking the form of either intermittent instillation of MMC or daily oral administration of 5-fluorouracil. Of 79 evaluable patients, 72 (91%) had received prior treatment for superficial bladder tumors, 69 (87%) had high-grade tumors, and 18 (23%) had non-papillary Tis. The overall response rate was 68%, made up of CR in 43 patients (54%) and partial response (PR) in 11 (14%). Patients with either five or more tumors or tumors larger than 1 cm showed a significantly lower response rate than those with fewer than five tumors and tumors smaller than 1 cm, respectively. There was no correlation between tumor growth pattern, tumor grade and response rate, though non-papillary Tis appeared to respond better than papillary tumors. A history of prior instillation therapy or of toxicity to this treatment had no significant influence on the response rate. Although no systemic toxicity was observed, 62 patients (74%) experienced cystitis and the treatment had to be discontinued within 4 weeks in 13 of 33 cases with severe symptoms. The preliminary conclusion of prophylactic treatment was that intermittent instillation of MMC was superior to 5-FU medication in reducing the recurrence rate for at least 2 years after the treatment.

Administration, Intravesical↗
PubMed1987

Prophylactic intravesical instillation therapy with adriamycin and mitomycin C in patients with superficial bladder cancer.

Intravesical instillation of adriamycin (ADM) or mitomycin C (MMC) was carried out for the purpose of preventing the recurrence of superficial bladder cancers (Ta and T1) after transurethral resection or transurethral coagulation. First, eligible patients were divided into two groups (solitary and multiple) and then they were randomized into the following three groups: (1) ADM group, intravesical instillation with 50 mg ADM dissolved in 100 ml physiological saline; (2) MMC group, intravesical instillation with 30 mg MMC dissolved in 100 ml physiological saline; (3) control, transurethral resection or transurethral coagulation alone. The drugs were given six times by instillation within 2 weeks after TUR or TUC; after 2 weeks the drugs were administered for 2 consecutive days every 4 weeks for 2 years. Of the 134 patients admitted to the study, 103 were evaluable and 31 were eliminated as non-evaluable patients. The cumulative nonrecurrence rates were 73.6% for ADM, 63.4% for MMC, and 22.5% for controls after a follow-up of 24 months. The cumulative non recurrence rates of the ADM and MMC groups were significantly higher than that of the control group. The incidence of side effects was low and the grade of these side effects mild. This instillation therapy with ADM and MMC was considered useful for preventing the recurrence of superficial bladder cancers.

Administration, Intravesical↗
PubMed1987

Mitomycin C, vinblastine and cisplatin combination chemotherapy in the treatment of advanced non-small cell lung cancer.

Thirty-one patients with previously untreated advanced non-small cell lung cancer were treated with mitomycin C (10 mg/m2, day 1), vinblastine (5 mg/m2, days 1 and 15), and cisplatin (80 mg/m2, day 1). Combination chemotherapy was repeated at 4-week intervals until disease progression or unacceptable toxicity. The overall response rate was 52.0%, with a median survival time of 8 months. The median duration of response was 16 weeks (range, 7-49 weeks), and 23% of the patients survived for more than 1 year. Toxicity included moderate myelosuppression, mild nephropathy, and severe nausea and vomiting. This combination therapy of anticancer agents appears to have antitumor activity, but not to have satisfactory therapeutic activity for advanced non-small cell lung cancer.

Adenocarcinoma↗
PubMed1984

Phase II study of hepatic artery infusion with 5-fluorouracil, adriamycin, and mitomycin C (FAM) in liver metastases from colorectal carcinoma.

Twenty-seven patients with liver metastases from colorectal carcinoma were treated with 5-fluorouracil, adriamycin, and mitomycin C (FAM) by hepatic artery infusion (HAI) every 2-3 months for a maximum of eight courses. Median survival for all patients was 22 months. Toxicity was acceptable and consisted in severe myelosuppression (8%), duodenal ulceration (8%), moderate nausea and vomiting (50%), and alopecia (100%). HAI with FAM is feasible and may have an impact on survival. Further studies are needed to determine the role of HAI, which may be of potential benefit to a substantial number of patients with metastatic colorectal carcinoma.

Adult↗
PubMed1983

Therapeutic effect of a retinoid (Ro 10-9359) on rats with bladder tumours induced by N-butyl-N-(4-hydroxybutyl)-nitrosamine upon administration alone or in combination with mitomycin C.

The therapeutic effect of an aromatic retinoic acid analogue (Ro 10-9359) and mitomycin C (MMC) on rats with bladder tumours induced by N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) was examined. Eight-week-old female Wistar rats were given 0.05% BBN in drinking water for 8 weeks. Therapy was started at week 26 and all rats were killed at week 30. MMC at a dose of 0.3 mg/kg twice a week ip for 3 weeks significantly reduced the incidence and the mean number of tumours. With oral Ro 10-9359 at a dose of 100 mg/kg once weekly for 4 weeks, no significant effect was observed. The combination of MMC and Ro 10-9359 significantly reduced the mean number, but not the incidence, of tumours. The difference between the effect of MMC alone and that of MMC given in combination with Ro 10-9359 was not statistically significant. Thus no favorable effect of the retinoid could be demonstrated either alone or in combination with MMC.

Animals↗