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At least 1,189 records · Page 66Linked to original sources
PubMed1988

5-Fluorouracil, high-dose folinic acid, and mitomycin C combination chemotherapy in advanced gastrointestinal adenocarcinomas. A pilot study.

Fifteen patients, median age 64 years, presenting with advanced gastrointestinal adenocarcinomas, were included in this study. The treatment combination consisted of folinic acid (200 mg/m2, IV bolus injection) followed by 5-fluorouracil (5-FU; 400 mg/m2, 30-min infusion) for 5 consecutive days and mitomycin C (10 mg/m2, IV bolus injection) on day 1, the therapy being resumed every 21 days. An objective response was noted in 7 of 15 patients (47%): 1 complete and 6 partial responses, including 4 of 5 patients who had received no prior chemotherapy and 3 of 10 patients who previously failed to respond to 5-FU. Objective responses were encountered in 4 of 7 stomach cancers, 2 of 3 pancreas tumors, and in only 1 of 5 colorectal carcinomas. Furthermore, 9 of 11 patients were completely relieved of their abdominal pain. The median duration of remission was 5 months. The median survival time of patients who responded to treatment was 7 months. Toxicity was acceptable, with mainly leukopenia and/or thrombocytopenia (5 patients) and oral mucositis (3 patients), leading to dose reduction. The combination of 5-FU+ folinic acid + mitomycin C appears to be a potentially effective regimen in the treatment of advanced gastrointestinal tumors, even in patients previously treated with 5-FU.

Adenocarcinoma↗
PubMed1989

Mitomycin C and vinblastine in advanced refractory breast cancer.

A combination of mitomycin C and vinblastine was administered as salvage treatment in 44 patients with heavily pretreated refractory breast cancer. Response rate was 23% (10 of 44) including one complete response of lung metastases. The highest response rate was seen in intrathoracic localizations (45%). Median duration of response was 6.5 months (range, 3+-17+). Treatment was generally well tolerated, and only 25% of patients developed nausea and vomiting. Neurologic toxicity was represented by paresthesia (8 patients) and constipation (one patient). Mild leukopenia was observed in 30 of 172 treatment cycles, but it exceeded grade 2 in only 5 patients. Considering the good compliance of this regimen and the poor prognosis of patients with advanced refractory disease, the combination of mitomycin C plus vinblastine appears to be useful as salvage treatment for metastatic breast cancer.

Adult↗
PubMed1990

Open phase II with 5-fluorouracil, 4-epi-doxorubicin and mitomycin C (FEM) in advanced gastric cancer.

Forty-four patients with advanced gastric cancer were treated with a combination including 5-fluorouracil, 4-epi-doxorubicin and mitomycin C. 4-Epi-doxorubicin was substituted for adriamycin in MacDonald's original schedule. The combined treatment involved 600 mg/m2 i.v. of 5-fluorouracil on days 1, 8, 29 and 36; 80 mg/m2 i.v. of 4-epi-doxorubicin on days 1 and 29; and 10 g/m2 i.v. of mitomycin C on day 1. The cycle was repeated on day 57 after the start of treatment. Out of 44 patients, 39 were evaluable. Thirteen partial remissions (33%) were achieved. The average duration of remission was 7 months (range, 3-12 months). The average survival of the responders was 9 months, and that of nonresponders 3.5 months. Toxicity was moderate, well-tolerated and, as compared with the FAM schedule, less pronounced, particularly as regards myelotoxicity. Thus, the substitution of 4-epi-doxorubicin for adriamycin in the original schedule of MacDonald et al. (1980) did not improve treatment results, but the observed toxicity was less pronounced.

Adenocarcinoma↗
PubMed1990

Cisplatin and mitomycin C in advanced chemotherapy-refractory breast cancer.

A combination of platinum (100 mg/m2 in a 24-h continuous i.v. infusion) and mitomycin C (10 mg/m2 i.v. push at the end of the cisplatin infusion) was administered in 20 patients with advanced breast cancer refractory to conventional treatments (CMF and anthracycline-containing regimens, hormonal therapies). The response rate was 20% (4/20), including one complete response of lung metastases which lasted 12 months. Median duration of partial responses was 4 months. Major toxicity was gastrointestinal and it was superimposable to that observed with other cisplatin-containing regimens. A marked and prolonged asthenia was reported in 6/20 patients (30%), and the regimen's compliance was poor. We conclude that at these doses and schedule, the cisplatin and mitomycin C combination has a limited efficacy in advanced breast cancer patients, and its use is not recommended in pretreated patients.

Adult↗
PubMed1985

A controlled evaluation of combined 5-fluorouracil, doxorubicin, and mitomycin C (FAM) for the treatment of advanced non-small-cell lung cancer.

One hundred eighty-six patients with advanced non-small-cell lung cancer were randomly assigned to treatment with combined 5-fluorouracil, doxorubicin, and mitomycin C (FAM) or combined methotrexate, doxorubicin, cyclophosphamide, and lomustine (MACC). Respective objective regression rates were comparable at 20% and 16%. Distribution of intervals to progression (overall median, 2.8 months) and survival times (overall median, 5.0 months) were essentially identical between the two regimens. The comparability of therapeutic effect was also evident within the subset of 81 patients who had adenocarcinoma cell type, although MACC showed a small advantage in survival after covariate analysis. In large-cell carcinoma, MACC showed a higher regression rate than that of FAM as well as a small advantage in survival. In squamous-cell carcinoma, however, FAM was superior to MACC in regression rates (32% v 4%) and also provided somewhat longer survival. With regard to toxicity, MACC produced a higher incidence of nausea and vomiting, whereas FAM produced more frequent and severe thrombocytopenia. From an overall standpoint, the therapeutic accomplishments of both regimens were disappointing. Our study does, however, provide additional evidence that mitomycin C-containing regimens may be selectively effective for squamous-cell carcinoma of the lung.

Adenocarcinoma↗
PubMed1990

Biliary excretion of mitomycin C dextran conjugates in relation to physicochemical characteristics of carrier dextran.

Biliary excretion characteristics of polymeric prodrugs of mitomycin C (MMC), mitomycin C-dextran conjugates with cationic or anionic charge (MMC-Dcat, MMC-Dan) and with different molecular weights of dextran (10,000, 70,000, and 500,000) were studied in rat. Following intravenous injection, bile was periodically collected and concentrations of free and dextran-conjugated MMC in it were determined by bioassay. MMC administered as a free form was excreted rapidly into bile and 1.8% of the dose was recovered within 2 h. A small amount of MMC was gradually excreted into bile after administration of all MMC-Ds and total recovery at 8 h was less than 1% of dose. In this case, a major part of excreted MMC was recovered as a conjugated form. MMC-Dcat gave a larger total excretion of MMC than MMC-Dan and excretion was also affected by the molecular weight of carrier dextran. The biliary recovery of MMC-Dcat labeled with 14C at a spacer moiety was significantly higher than that of conjugated MMC determined by bioassay suggesting release and/or inactivation of MMC in MMC-D during the circulation in the body. These results were compared with biliary excretion of model macromolecules with the same molecular weight but different electric charge in order to clarify the effect of electric charge on the biliary excretion of macromolecules. Cationic macromolecules exhibited higher biliary excretion in relation to greater hepatic uptake.

Animals↗
PubMed1984

Growth-inhibition of leukemia L-1210 ascites tumor by combination of carrageenan and mitomycin C in vivo.

A purified i-carrageenan prepared by means of pronase digestion and fractional precipitation with KCl was investigated for its growth-inhibitory effect on mouse leukemia L-1210 transplanted in (C57BL/6 x DBA/2)F1 (BDF1) mice. This carrageenan specimen was not growth-inhibitory on this tumor when it was administered alone in a dose of 0.1 to 10 mg/kg/d, 4 times. However, in combination, with a small amount of mitomycin C, 0.25 mg/kg/d, a remarkable tumor growth-inhibition has manifested affording a complete regression of this tumor. Acid phosphatase alpha-galactosidase and active oxygen generation activities of the peritoneal exudate cells in the carrageenan-administered mice were remarkably higher than those of the control mice. Therefore, the booster effect of this carrageenan preparation on antitumor activity of mitomycin C is assumed to be associated with the inflammatory activity of this sulfated polysaccharide.

Acid Phosphatase↗
PubMed1986

Interactions of anticancer quinone drugs, aclacinomycin A, adriamycin, carbazilquinone, and mitomycin C, with NADPH-cytochrome P-450 reductase, xanthine oxidase and oxygen.

The properties of the interactions of anticancer quinone drugs, aclacinomycin A, adriamycin, carbazilquinone, and mitomycin C with nicotinamide adenine dinucleotide phosphate (NADPH)-cytochrome P-450 reductase and xanthine oxidase under anaerobic and aerobic conditions were studied. Km values of NADPH-cytochrome P-450 reductase for these drugs were in the range of 40-227 microM, and that of deflavo xanthine oxidase in the range of 39-over 200 microM. Under anaerobic conditions, when xanthine was used as an electron donor, deflavo xanthine oxidase catalyzed the reductive glycosidic cleavage reaction of anthracyclines and nicotinamide adenine dinucleotide was ineffective as an electron donor. In the electron spin resonance study, the formation of the semiquinone or free radical state of the quinone drugs in both enzyme systems were evidenced. A weak and symmetric signal was obtained from aclacinomycin A, and a symmetric signal from adriamycin was changed into an asymmetric and strong. The hyperfine structure was obtained from carbazilquinone in the oxidase system. In the studies of ultraviolet-visible spectra of the quinone drugs in the reductase system, the spectra of aclacinomycin A and adriamycin were changed to their 7-deoxylaglycones, and the formation of small amounts of the fully reduced form were observed after long incubations. The spectrum of carbazilquinone was changed to the hydroquinone form and mitomycin C was converted into mitosene analogues. Under aerobic conditions, superoxide radicals and hydrogen peroxide were effectively produced in the presence of anticancer quinone drugs in both enzyme systems. The superoxide-dependent hydroxy radical production, which was measured by ethylene production from methional, was observed in the presence of aclacinomycin A and adriamycin in the deflavo xanthine oxidase system. From these results, the possible reactions in the interactions of anticancer quinone drugs with these enzymes and oxygen are discussed.

Aclarubicin↗
PubMed1991

Concomitant pelvic irradiation, 5-fluorouracil and mitomycin C in the treatment of advanced cervical carcinoma.

This was a Phase II study of 24 late (FIGO) Stage IIb and 39 Stage III patients. External beam radiotherapy was given daily, five days a week, using 15 x 15 cm parallel opposed pelvic fields. The first 20 patients had 45.00 Gy mid-plane dose in 20 fractions, Days 1-28, the last 43 patients had 50.40 Gy in 28 fractions, Days 1-43. This was followed by an intracavitary boost of 17.00 Gy to Point A in two fractions over seven days. The first seven patients had concomitant 5-fluorouracil (5FU) 1 g/m2/day (maximum 1.5 g/day) Days 2-5, 30-33 and 57-60, with mitomycin C 10 mg/m2 (maximum 15 mg) Days 2 and 57. Two patients had WHO Grade 4 cytopenia, and only two were able to have full dose intensity. The 5FU dose was reduced to 0.8 g/m2/day, for Days 2-5 and 30-33; mitomycin C was given on Day 2 only. Treatment morbidity with the reduced chemotherapy intensity was comparable with that of radiotherapy alone. Median follow-up was 16 months (range 6-44). Median survival was 35 months. The results were compared with historical controls treated using the same radiation method alone. Two-year survival for late Stage IIb patients was 67% with the combination and 72% with radiotherapy alone; for Stage III, 67% and 49% respectively. Two-year pelvic control for late Stage IIb was 87% (combination) and 84% (radiotherapy alone) and for Stage III, 61% and 55% respectively. In contrast to reports from other centres, these results do not show an overall significant improvement on radiotherapy alone. A Phase III study may not be practicable.

Adult↗
PubMed1986

Pulmonary hypertension, hemolytic anemia, and renal failure. A mitomycin-associated syndrome.

After treatment with mitomycin C, a patient developed pulmonary hypertension with interstitial infiltrates, microangiopathic hemolytic anemia, systemic hypertension, and renal failure with the nephrotic syndrome. Open lung biopsy documented intracapillary fibrin thrombi in the pulmonary vasculature. Renal biopsy documented glomerular and arteriolar changes that were most consistent with a thrombotic-thrombocytopenic-like process. Treatment with corticosteroids, fresh-frozen plasma, and total plasma exchange was ineffective. The patient died six months after the onset. When mitomycin-C therapy is given, the clinician should be aware of the pulmonary, renal, and microangiopathic changes that can be associated with such therapy.

Adenocarcinoma↗
PubMed1982

The action of 7-N-(p-hydroxyphenyl)mitomycin C [M-83] in suppressing murine immune response.

The immuno-suppressive activities of 7-N-(p-hydroxyphenyl)mitomycin C [M-83], a derivative of mitomycin C (MMC), which has better antitumor activity against murine tumors, was investigated in mice. A single injection of M-83 induced an apparent but relatively transient reduction in both plaque-forming cell production and delayed type hypersensitivity reaction to sheep red blood cells. The suppressive effect of M-83 was significantly milder than that of MMC at the same effective and molar equivalent doses. Moreover, the recovery from immunosuppression induced by M-83 was also relatively rapid as compared with MMC. The inhibiting activity of M-83 against the blastogenic response of spleen cells was milder in vivo, but was more significantly cytotoxic in vitro than that of MMC.

Animals↗
PubMed1982

Phage inactivation and DNA strand scission activities of 7-N-(p-hydroxyphenyl)mitomycin C.

A new derivative of mitomycin C (MMC), 7-N-(p-hydroxyphenyl)mitomycin C (M-83), had higher phage inactivation activity against phages phiX174 and PM2 than MMC, and also higher DNA strand scission activity against their single- and double-stranded DNAs. M-83, at one third to one sixth concentration of MMC, showed the same level of phage inactivation and DNA strand scission activities. The mechanism of phage inactivation and DNA strand scission by M-83 were similar to those of MMC: (1) Reduction of M-83 was required for its action. (2) Oxygen radicals were involved in DNA strand scission, and metal ions possibly participated in the generation of oxygen radicals. (3) DNA strand scission was single strand scission, and dependent on temperature. The high DNA strand scission activity of M-83 is considered to reflect the rapid conversion to the active form.

Bacteriophage phi X 174↗
PubMedDate not supplied

Experimental tumor inhibitory and toxic properties of the mitomycin A analogue 7-(2-hydroxyethoxy) mitosane (BMY-25551).

BMY-25551, 7-(2-hydroxyethoxy)mitosane, was selected from a series of mitomycin A (MMA) analogues for more detailed study. As with other members of this class, it was shown to be 8 to 20 times more potent than mitomycin C (MMC) in cytotoxicity to murine and human tumor cell lines in vitro, in causing DNA cross links in vitro, and in dose levels for tumor inhibition in vivo. BMY-25551 appeared to be more effective in tumor inhibition than MMC against P388 leukemia and B16 melanoma in mice and comparable to MMC against L1210 leukemia and Madison 109 lung carcinoma. BMY-25551 was also comparable to MMC in hematologic depression in mice. Factors affecting its possible utility in humans are discussed.

Animals↗
PubMed1991

Effect of deficiencies in DNA repair on the toxicity of mitomycin C and porfiromycin to CHO cells under aerobic and hypoxic conditions.

A wild type Chinese hamster cell line (AA8) and three repair-deficient sublines of AA8 (EM9, UV4, and UV5) were used to study the nature of the cytotoxic lesions produced by the bioreductive alkylating agents mitomycin C and porfiromycin under aerobic and hypoxic conditions. The sensitivities of the repair-deficient sublines to the drugs varied markedly: EM9 was similar to AA8, whereas UV4 was exquisitely sensitive and UV5 was of intermediate sensitivity. Moreover, both the relative toxicities of the two drugs and the relative toxicities of each drug under aerobic and hypoxic conditions varied for the different cell lines. These data suggest that there are differences in the spectra of toxic lesions produced by mitomycin and porfiromycin and that there are differences in the lesions produced by these drugs under aerobic and hypoxic conditions.

Aerobiosis↗
PubMed1991

[In vivo assessment on the therapeutic effects of etoposide, vincristine and mitomycin C against human neuroblastoma].

Anti-tumor effects of etoposide (VP-16), vincristine and mitomycin C were evaluated with four human neuroblastoma xenograft, according to Battelle Columbus Laboratories protocol. Etoposide is one of the agents which has been reported to be effective against advanced neuroblastoma clinically, if combined with other agents. While vincristine was effective against 1 out 4 neuroblastoma xenografts, TS-N-2, with 58.1% maximum inhibition rate, etoposide was assessed ineffective as a single agent in all of the 3 xenografts used. Since etoposide had no effect on the weight gain in nude mice in this xenograft experiment, the dose of etoposide was increased two-fold against 2 xenografts, but found ineffective also in the increased dose. Mitomycin C, which has not been used in childhood malignant tumors, was effective against 2 out of 4 xenografts, TNB-9 and SK-N-AS, with 72.0% and 78.4% maximum inhibition rates, respectively.

Animals↗
PubMed1991

[Pharmacokinetics and local availability of mitomycin. The influence of vasoconstriction and chemoembolization].

The influence of the vasopressin-pro-drug glycylpressine (GP) and of a chemoembolisation with Spherex starch-particles (SP) on the availability of mitomycin (CAS 50-07-7, mitomycin C, MMC) was investigated in 30 patients with liver metastases, MMC administration was performed after blocking of the common hepatic artery by different concentrations of SP and after different time-intervals of GP. The comparison of plasma-levels after bolus injection without GP and after administration of MMC after 2, 5 and 15 min of vasoconstriction and after chemoembolisation with 450 mg or 900 mg SP, respectively, showed a remarkable reduction in the systemic circulation of MMC in the blood vessel system at about 40% (GP) and 45% (SP). A statistically significant influence on the pharmacokinetics of MMC with regard to CO, Vd, T 1/2zp, AUC and Cl(tot) was found, but not in t1/2el, t1/2biol and Vl. Both methods cause a distinctly accelerated diffusion of MMC into the tissue of the tumor region by change of the hemodynamics, leading to lowered side-effects. Thus the clinical picture was improved by MMC.

Biological Availability↗
PubMed1990

[Uremic hemolytic syndrome induced by mitomycin C. Presentation of a series of 5 cases and review of the literature].

Five new cases of hemolytic uremic syndrome associated mitomycin C treatment in neoplastic patients are presented and clinical, biological, histological therapeutic and the evolution data of 92 other cases from the literature are analyzed. The results point out the high incidence of GI adenocarcinomas (65%), its rare appearance with total mitomycin doses below 50 mg/m2, its frequent clinical presentation with cardiovascular manifestations, the therapeutical difficulties and the possibility of a better prognosis with an early diagnosis.

Adenocarcinoma↗
PubMed1990

Decreased NADPH:cytochrome P-450 reductase activity and impaired drug activation in a mammalian cell line resistant to mitomycin C under aerobic but not hypoxic conditions.

Mitomycin C (MMC) is regarded as the prototype bioreductive alkylating agent in clinical use. To elucidate the biochemical basis of MMC resistance, we isolated a drug resistant derivative (designated CHO-MMC) of a Chinese hamster ovary cell line (CHO-K1) by exposure to progressively higher concentrations of MMC. CHO-MMC cells exhibited a 17-fold increase in resistance to MMC and were 33-fold cross-resistant to the monofunctional derivative, decarbamoyl mitomycin C. In contrast, CHO-MMC cells showed only a 2-fold level of resistance to BMY 25282, a more easily activated analogue of MMC, and exhibited parental sensitivity to MMC under radiobiologically hypoxic conditions. CHO-MMC cells showed no increased resistance to a range of DNA damaging agents including several other alkylating agents (e.g., melphalan and methyl methanesulfonate). Cross-resistance to drugs associated with the multidrug resistant phenotype (e.g., Adriamycin and vincristine) was present only at very low levels. Using a specific high performance liquid chromatography technique, we examined the rates of reduction of MMC and BMY 25282 in cell extracts from CHO-K1 and CHO-MMC cells under both aerobic (air) and hypoxic (N2) conditions. Reduction rates for both drugs were at least 30-fold faster under nitrogen than in air. Metabolism of MMC was undetectable in air but was readily detectable under nitrogen and was 2- 3-fold slower in CHO-MMC cell extracts than in CHO-K1 cell extracts. Although BMY 25282 was more readily reduced under nitrogen, no difference was detected between extracts from CHO-K1 or CHO-MMC cells in the rate of reduction of BMY 25282 under either air or nitrogen. The activity of NADPH:cytochrome P-450 (cytochrome c) reductase, an enzyme implicated in the bioreductive activation of MMC, was 3-4-fold lower in CHO-MMC cells than in the parental line. These findings suggest that the resistance of CHO-MMC cells to MMC under aerobic conditions may be due to impaired metabolic activation of the drug as a result of a decrease in NADPH:cytochrome P-450 reductase activity. This supports the view that decreased bioreductive enzyme activity may be a significant mechanism for acquired resistance to MMC in tumor cells in vivo and that more readily activated analogues may be potentially useful in overcoming this specific form of resistance.

Aerobiosis↗