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PubMed1984

Studies of mitomycin C absorption after intravesical treatment of superficial bladder tumors.

Mitomycin C is an active drug in the treatment of superficial bladder cancer. Although clinical safety of intravesical mitomycin C has been well accepted there are no data on absorption of this drug from the bladder in patients with damaged bladder mucosa. We studied 18 patients for evidence of absorption of mitomycin C after transurethral resection and/or radiation therapy. Mitomycin C is absorbed on intravesical instillation and the degree of absorption depends on the degree of damage to the bladder. Despite some evidence of absorption no systemic effect on bone marrow was observed and no evidence of deoxyribonucleic acid damage was found in any of these patients. Mitomycin C appears to be a safe drug but further studies are indicated to document its safety when used for maintenance therapy.

Antibiotics, Antineoplastic↗
PubMed1982

Intravesical therapy of low stage bladder carcinoma with mitomycin C: comparison of results in untreated and previously treated patients.

There were 28 patients with superficial bladder carcinoma (Ta, Tl or TIS) entered into protocols for intravesical therapy with mitomycin C. Of the 28 patients 16 had failed previously on thio-tepa (group A), 7 had responded successfully to thio-tepa (group B) and 5 had never received thio-tepa (group C). There were 5 complete responses and 9 failures to mitomycin C therapy in group A. There were 5 and 4 complete responses to mitomycin C therapy in groups B and C, respectively. The treatment plan consisted of the instillation of 40 mg. mitomycin C in 40 cc water weekly for 8 weeks. Because of severe local irritative symptoms 3 of the 28 patients did not complete the course of therapy. In another patient a diffuse body rash developed after the third instillation. Mitomycin C seems effective in ablating low stage bladder carcinoma, although it is less effective in patients who have failed prior thio-tepa therapy.

Adult↗
PubMed1985

In vivo efficacy and ultrastructural effects of mitomycin C against experimental alveolar hydatid disease.

The in vivo efficacy and ultrastructural effects of mitomycin C were determined against alveolar hydatid disease in experimentally infected animals and compared to mebendazole treatment. Mitomycin C inhibited the mean cyst mass of treated versus control animals by 84.1% which was statistically significant at the alpha = 0.01 level. Mebendazole given daily inhibited the mean cyst mass by 80.1%, while mebendazole administration on the same treatment schedule as that used for mitomycin C inhibited the mean cyst mass by 70.4%. Ultrastructurally, mitomycin C was not observed to affect the tegumental microtriches (microvilli) or the microtubular system. However, an increase in the number and accumulation of round to oval electrondense vesicles was observed within the subtegument. These inclusion bodies became vacuolated, subsequently degenerated, and formed myelin-like figures. Mitomycin C, like mebendazole, was only cystistatic in its effects on the cyst stage of Echinococcus multilocularis as evidenced by the growth of treated cyst material following inoculation into helminth-free animals.

Animals↗
PubMed1986

Autocatalytic quinone methide formation from mitomycin c.

Mitomycin c in the presence of NADPH and brewers' yeast NADPH: (acceptor) oxidoreductase (Old Yellow enzyme, EC 1.6.99.1) is transformed, at pH 8.0 and with anaerobicity, to two major mitosene products (the cis- and trans-1-hydroxy-2,7-diaminomitosenes; respective yields of 45 and 30%). These arise by covalent trapping by solvent of a quinone methide intermediate, obtained by rearrangement of the mitomycin c hydroquinone. At lower pH (6.5), the major product of this reaction is 2,7-diaminomitosene, which arises by covalent trapping of the quinone methide by H+. In the former instance the quinone methide acts as an electrophile and in the latter as a nucleophile. A detailed kinetic analysis indicates that the role of the NADPH and Old Yellow enzyme is to initiate an autocatalytic reaction, propagated by mitomycin c reduction by the mitosene hydroquinones (arising by the electrophilic pathway). The evidence supporting this conclusion is the formation of oxidized mitosene products, under the rigorously anaerobic reaction circumstance, the nonstoichiometric participation of NADPH, a dependence of the velocity on the total mitomycin c concentration, the pH dependence of the reaction, and the accurate simulation of the overall kinetic course with a mathematical model of the autocatalytic pathway. These observations indicate that the autocatalytic pathway may be dominant during in vitro mitomycin c anaerobic reductive activation by other reducing agents and that (as with anthracycline reductive activation) oxidation of the mitosene hydroquinone obtained from nucleophile addition to the quinone methide may be a necessary event for the formation of stable covalent adducts in vivo.

Anaerobiosis↗
PubMed1981

Reductive metabolism and alkylating activity of mitomycin C induced by rat liver microsomes.

Mitomycin C, an antitumor antibiotic, is rapidly metabolized in the presence of rat liver microsomes. NADPH and anaerobic conditions are required for the process. The products isolated after reexposure to air are 2,7-diaminomitosene derivatives. Specifically, in the presence of inorganic phosphate, 1,2-cis- and -trans-2,7-diaminomitosene 1-phosphates, 1,2-cis- and -trans-2,7-diamino-1-hydroxymitosenes, and 2,7-diaminomitosene are formed. The last substance is a new mitomycin C derivative, and proof for its structure is presented. Mytomycin C has been previously postulated to be an alklating agent requiring reduction for activity (Iyer, V. N., & Szybalski, W. (1964) Science (Washington, D.C.) 145, 55]. The 1-phosphates above represent the first chemically characterized bioreductive alkylation products of the drug. 5'-Uridylic acid is alkylated analogously under these conditions, to give cis- and trans-2,7-diaminomitosene 1-(5'-uridylate), while the phosphodiester UpU and uridine itself are inert. Hydrogen gas/PtO2 gives the same results as microsomes/NADPH. The formation of the observed compounds indicates that enzymatic (or chemical) reduction of the quinone system of mitomycin C induces ring opening of the aziridine function, generating a reactive center at the C1 position as previously postulated by others (ibid.). The second alkylating center, also postulated, is not evident, however, under the conditions tested, indicating that the aziridine is the primary bioreductive alkylation function of mitomycin C. Identification of the products and mechanism of the microsomal anaerobic metabolism of mitomycin C are significant in view of the reported toxicity of the drug to anaerobic cancer cells.

Alkylation↗
PubMed1984

Mitomycin C analogues with aryl substituents on the 7-amino group.

A series of 30 different N7-phenyl-substituted mitomycin C analogues, including 25 new compounds, was prepared from mitomycin A. Seven of these compounds were clearly superior to mitomycin C in activity against P-388 murine leukemia. The para- and the meta-substituted derivatives were subjected to Hansch analysis, which revealed that the lipid-water distribution coefficient pi was the only significant factor in determining antitumor potency (MED). The substituent electronegativity factor sigma was statistically insignificant in determining potency, despite the good correlation of sigma p with the polarographic quinone-reduction potential. These results suggest that diffusion into the tumor cell or access to the receptor is more important than bioreductive activation in determining antitumor potency for this particular group of mitosanes . Fifteen new mitomycin C analogues with heterocycles on the 7-amino group also were prepared. Two of them, containing pyrazolyl and aminopyridyl substituents, were more active than mitomycin C against P-388 murine leukemia. No broad correlations could be made among the antitumor potencies and physicochemical properties for this type of analogue.

Animals↗
PubMed1987

Mitomycin-C and metronidazole in the treatment of advanced renal-cell carcinoma.

Fifteen patients with advanced renal-cell carcinoma were treated with the combination of mitomycin-C 14-20 mg/m2 i.v. every 7 weeks and metronidazole 1,500 mg/m2 p.o. 12 and 1 h before and 6 and 24 h after the mitomycin-C. Of 12 patients evaluable for response, three (25%) responded with partial remissions. Myelosuppression did not appear to be increased over that seen with mitomycin-C alone. Pulmonary toxicity occurred in three patients and was fatal in two. The incidence of pulmonary toxicity was probably increased over that seen with mitomycin-C alone. Renal toxicity was also seen. Based on this small study, it was our feeling that this dose-schedule of metronidazole did not appear to result in enough of an augmentation of the efficacy of mitomycin-C against renal-cell carcinoma to justify the incidence of serious toxicity.

Adult↗
PubMed1987

Mitomycin C-treated 3T3 fibroblasts used as feeder layers for human keratinocyte culture retain the capacity to generate eicosanoids.

Murine 3T3 fibroblasts, treated with mitomycin C in order to inhibit their proliferation, have been extensively used as feeder layers to enhance the cultivation of human keratinocytes in vitro. In order to identify possible factors responsible for this enhancing effect, studies were undertaken to determine whether eicosanoid generation by 3T3 cells was preserved following mitomycin C treatment. Accordingly, both untreated and mitomycin C-treated 3T3 cells were incubated with [1-14C]arachidonic acid and their qualitative generation of [1-14C]labeled eicosanoids assessed by thin layer chromatography. Levels of endogenously generated eicosanoids were quantitatively determined by specific radioimmunoassays performed on culture supernatants obtained from incubations of both treated and untreated cells. Results of these studies demonstrate that mitomycin C treatment, although preventing the proliferation of 3T3 cells, failed to alter their generation of prostaglandin E2 or 6-keto-prostaglandin F1 alpha. Furthermore, in parallel cultures, the untreated 3T3 cells stopped generating eicosanoids upon reaching confluence, whereas the mitomycin C-treated 3T3 cells that did not proliferate continued to generate eicosanoids.

Animals↗
PubMed1993

Experience with mitomycin in the treatment of non-small cell lung cancer.

Mitomycin has proven to be among the most active drugs available for the single-agent treatment of non-small cell lung cancer (NSCLC). In combination with vinca alkaloids and cisplatin, mitomycin can produce response rates greater than or equal to 50% in properly selected patients. In our experience, such responses were achieved using moderate doses (7 or 8 mg/m2) of mitomycin, which also resulted in fewer hematologic and other toxicities. Delivery of MVP (mitomycin/vinca alkaloid/cisplatin) to 150 patients with stages III and IV NSCLC during the last decade showed maximal response was achieved after two or three cycles of therapy. A comparative analysis of results reported using MVP regimens suggests that high response rates are associated with greater dose-intensive use of cisplatin and lesser dose-intensive use of mitomycin. Although the role of MVP in the treatment of advanced NSCLC is unclear, use of mitomycin-containing regimens as part of a multidisciplinary approach to stage IIIA NSCLC has yielded high response rates and has successfully downstaged patients prior to surgery. Randomized clinical trials will be required to validate these findings, but the focus of future research should be on discovering new agents with greater activity and on developing new approaches wherein these agents can be delivered with maximum efficacy and minimum toxicity.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1983

Interaction between doxorubicin and mitomycin C on mortality and myocardial contractility in guinea pig.

The present investigations were carried out in guinea pig to ascertain whether mitomycin C has a direct cardiotoxic effect or interacts with doxorubicin-induced cardiotoxicity. I.p. administration of mitomycin C did not modify the survival rate up to 30 days, whereas the combined administration of doxorubicin and mitomycin C significantly decreased the survival time in comparison to the doxorubicin-treated group. On isolated atria, mitomycin C did not cause significant inhibition of the contractile force or an enhancement of the doxorubicin-induced negative inotropic effect. These results do not support the possibility that mitomycin C potentiates the acute cardiotoxic effects produced by doxorubicin.

Animals↗
PubMed1986

Random prospective study of vindesine versus vindesine plus high-dose cisplatin versus vindesine plus cisplatin plus mitomycin C in advanced non-small-cell lung cancer.

In this phase III randomized study, 124 evaluable patients with unresectable non-small-cell lung cancer (NSCLC) were randomized to vindesine v cisplatin (120 mg/m2) plus vindesine v cisplatin (60 mg/m2) plus vindesine plus mitomycin C. The objective response rate for cisplatin and vindesine was 27% v 20% for cisplatin, vindesine, and mitomycin C, and 14% for vindesine alone (P = .25 for cisplatin and vindesine v vindesine). The percentage of patients having stable disease (no progression for a minimum of 3 months) was 20% (cisplatin and vindesine), 27% (cisplatin, vindesine, and mitomycin C), and 26% (vindesine alone), respectively. The median survival time for vindesine was 18 weeks, compared with 26 weeks for cisplatin and vindesine and 17 weeks for cisplatin, vindesine, and mitomycin C. Overall survival was not statistically different for cisplatin plus vindesine v vindesine (P = .65). There was no evidence for improved duration of remission or survival of responders with the cisplatin (120 mg/m2) and vindesine arm. This study failed to demonstrate sufficient therapeutic benefit for cisplatin and vindesine (+/- mitomycin C) compared with single-agent vindesine to justify the increased cost and toxicity of these combination regimens.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1984

Antitumor activity of lipophilic prodrugs of mitomycin C entrapped in liposome or O/W emulsion.

Nine lipophilic la-N-substituted prodrugs of mitomycin C were formulated in lipid dispersion dosage forms and their fundamental antitumor activities were evaluated. The prodrugs were efficiently incorporated into liposome or O/W emulsion according to their increased lipophilicities , while mitomycin C was hardly entrapped into them. Almost complete incorporation was observed in nonyloxycarbonyl and cholesteryloxycarbonyl mitomycin C which showed partition coefficients over 8000 in chloroform/water system. The release rate from these dosage forms determined by a dynamic dialysis method decreased with an increase in the partition coefficients of the derivatives. All prodrugs entrapped in liposome or O/W emulsion showed significant antitumor activities against L1210 leukemia in i.p.-i.p. system except for cholesteryloxycarbonyl mitomycin C. In spite of considerable antitumor activities showen in the forms of liposome and emulsion, saline suspension of nonyloxycarbonyl mitomycin C failed to exhibit any activity because of its poor aqueous solubility. These results suggested the utility of the combining delivery system of lipophilic prodrug with physical device such as liposome and O/W emulsion.

Animals↗
PubMed1987

Mitomycin C associated hemolytic uremic syndrome.

Mitomycin C associated Hemolytic Uremic Syndrome (HUS) is a potentially fatal but uncommon condition that is not yet widely recognised. It consists of microangiopathic hemolytic anemia, thrombocytopenia and progressive renal failure associated with mitomycin C treatment and affects about 10% of patients treated with this agent. The renal failure usually develops about 8-10 mth after start of mitomycin C treatment and the mortality is approximately 60% from renal failure or pulmonary edema. Renal lesions are similar to those seen in idiopathic HUS and include arteriolar fibrin thrombi, expanded subendothelial zones in glomerular capillary walls, ischemic wrinkling of glomerular basement membranes and mesangiolysis. The mechanism of action is postulated as mitomycin C-induced endothelial cell damage. We describe the clinical course and pathological findings in a 65 yr-old man with gastric adenocarcinoma who developed renal failure and thrombocytopenia while on treatment with mitomycin C and died in pulmonary edema.

Aged↗
PubMed1991

Chinese hamster ovary cell lines resistant to mitomycin C under aerobic but not hypoxic conditions are deficient in DT-diaphorase.

We have previously reported the isolation of CHO cell lines resistant to mitomycin C under aerobic conditions of drug exposure. Here it is reported that these cell lines have the same response to mitomycin C under hypoxic conditions as do controls. The cells are shown to have lower levels of DT-diaphorase activity than controls, but similar levels of activity of NADPH:cytochrome c reductase, another enzyme involved in the metabolism of mitomycin C. Evidence for molecular defects in the DT-diaphorase gene or gene transcript is presented for the deficient cell lines. The consequences of this DT-diaphorase deficiency is further explored by testing the toxicity of menadione, an established enzyme substrate. The isolation of CHO cell lines deficient in DT-diaphorase activity and resistant to mitomycin C under aerobic but not hypoxic conditions suggests that mitomycin C reduction by this enzyme has a significant impact on cytotoxicity under aerobic but not hypoxic conditions. Similarly, DT-diaphorase metabolism of menadione does not appear to have a significant impact on cytotoxicity in CHO cells.

Animals↗
PubMed1989

Effect of the superoxide dismutase inhibitor, diethyldithiocarbamate, on the cytotoxicity of mitomycin antibiotics.

Mitomycin C (MC) and its structural analogs porfiromycin (PM), BMY-25282 and BL-6783 are toxic to EMT6 cells under aerobic and hypoxic conditions. The mitomycin antibiotics are hypothesized to exert cytotoxicity under hypoxic conditions by cross-linking DNA following reductive activation, while aerobic cytotoxicity may involve DNA cross-linking by these agents and/or damage due to the generation of oxygen radicals. Previous findings (Pritsos and Sartorelli, 1986) indicated that the rank order of cytotoxicity for a series of mitomycins was the same as the rank order for the rate of oxygen consumption induced by these agents. As an additional approach to explore the role of oxygen radicals in the aerobic cytotoxicity of the four agents studied, EMT6 cells were treated with the mitomycins in the presence of the superoxide dismutase inhibitor diethyldithiocarbamate (DETC). DETC, which decreased superoxide dismutase activity in EMT6 cells, increased the cytotoxicity of BMY-25282 and BL-6783 by half an order of magnitude, but did not affect the toxicity of PM or MC to these cells. DNA cross-links, a proposed cytotoxic lesion induced by BMY-25282, however, were not detectably increased in EMT6 cells exposed to this agent in the presence of DETC in spite of the large increase in cytotoxicity under these treatment conditions. No single strand breaks were detected in cells exposed to either BMY-25282 or BMY-25282 plus DETC. The findings support the concept that oxygen radicals may have a role in the aerobic cytotoxicity of some of the mitomycin antibiotics, and that the lesions responsible for cytotoxicity produced by oxygen radicals may not reside entirely at the level of DNA.

Aerobiosis↗
PubMed1987

[A randomized trial comparing vindesine plus cisplatin with mitomycin C, vindesine plus cisplatin in patients with advanced non-small cell lung cancer].

Thirty-six evaluable patients with advanced non-small cell lung cancer were randomized to treatments involving vindesine (3 mg/m2 X 3) plus cisplatin (80-120 mg/m2) versus mitomycin C (8 mg/m2) plus vindesine (2 mg/m2 X 3) plus cisplatin (80-120 mg/m2). The response rate for the vindesine and cisplatin combination was 29%, versus 47% for the mitomycin C, vindesine and cisplatin combination. There was no evidence of improved duration of response in patients given mitomycin C, vindesine and cisplatin. The median survival for patients given mitomycin C, vindesine and cisplatin was 11.4 months, compared with 10.3 months for those given vindesine and cisplatin. Toxicity was almost comparable for the two treatments. The utility of addition of mitomycin C to vindesine and cisplatin should be evaluated in further investigations.

Adult↗
PubMed1985

Phase I study of hepatic arterial degradable starch microspheres and mitomycin.

Intraarterial administration of 40-microns degradable starch microspheres (DSM) in a drug solution can temporarily retard flow of the drug-blood column through the arteriolar-capillary bed and lead to increased local drug deposition. Premonitory to Phase II-III efficacy studies applying this concept to regional therapy, it was necessary to determine the DSM dose to use. Patients with hepatic cancers were treated with varying doses of DSM with mitomycin C coadministered into the hepatic artery to define a dose of DSM which produces acceptable toxicity with maximal hepatic drug deposition as determined by a reduction in systemic mitomycin C exposure. Comparison of six patients receiving 6 ml of DSM (6 X 10(6) particles/ml) with ten patients receiving 15 ml showed a lower incidence and decreased severity of acute toxicity in terms of nausea/vomiting (16% versus 50%) and right upper quadrant hepatic pain (none versus 40%) with 6 ml of DSM. Reduction in systemic mitomycin C exposure evaluated by decrements in the area under the concentration curve in peripheral blood with time due to DSM was similar in both groups. Another seven patients were treated with escalating doses of DSM concurrently with 5 mg of mitomycin C. Although all seven patients tolerated 6 ml of DSM, higher doses (9 ml, 12 ml, 15 ml) led to incremental patient drop-out due to severe, acute right upper quadrant pain with only two patients able to receive 15 ml of DSM. In these patients, 6 ml of DSM appeared nearly equivalent to higher doses in terms of systemic exposure to mitomycin C. Eleven additional patients were evaluated for tolerance to repeated 6-ml dosing of DSM. Four patients had epigastric pain correlating with flow to the stomach demonstrated by nuclide angiography. The seven patients with no pain and no flow to stomach were treated with good tolerance for three-plus courses. Thus, 6 ml of DSM appear to be appropriate for Phase II-III studies.

Adult↗
PubMedDate not supplied

[Variability of beta-1,3/1,4-glucanglucanohydrolase-forming Streptomyces narbonensis induced by UV rays and mitomycin C].

The effect of mitomycin C and UV on spores before germination and two hours after it was investigated with Streptomyces narbonensis 2a producing beta-1,3/1,4-glucanglucan hydrolase (beta-glucanase). The lethal effect of mitomycin C on the germinating spores was considerably greater than that on the spores. The mutagenic activity of mitomycin C was closely related to the process of spore germination. The frequency of mutations was higher when mitomycin C acted on germinated spores. UV caused a lesser frequency of morphological mutations than mitomycin C did. The action of UV produced mutants which synthesized beta-glucanase of the exotype in the course of fermentation in a medium without an inductor.

Enzyme Induction↗