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At least 19 recordsLinked to original sources
PubMed1976

H2O2 generation during the redox cycle of mitomycin C and dna-bound mitomycin C.

Reduction of mitomycin C by NaBH4 or by NADPH in the presence of a cell extract followed by exposure to air results in the generation of H2O2. This phenomenon occurs not only with free mitomycin but also with mitomycin irreversibly bound to DNA. In view of these findings, the antibiotic activity of mitomycin was tested in two bacterial systems: a facultative aerobic bacterium grown in the presence or absence of oxygen and obligate anaerobic bacterium. No oxygen effect could be demonstrated in either case in the growth-inhibitory and bactericidal activity of the drug. Nevertheless, the H202 generating capacity of mitomycin-DNA complexes inside the nucleus may play a role in the drug-induced biological damage to the genetic material of cells.

Aerobiosis↗
PubMed1975

Autoradiographic study of chick limb cartilage in vivo and in vitro and its response to mitomycin C (MMC).

Effect of mitomycin C on mucopolysaccharide synthesis by the cartilage cells of chick limb bud (5-9 days old) was investigated both in vivo and in vitro by the uptake study of 35S. Control specimens (both in vivo and in vitro) showed higher concentration of silver grains, mostly intercellular, in the initial stages. Hypertrophy of cartilage cells at later stages reduced the matrix, leading to a corresponding decrease in the accumulation of silver grains. In the treated groups, both in vivo and in vitro, the silver grains were found to be less in number during the initial stage of growth than in the corresponding controls, due to the suppressive effect of the mitomycin C. However, during the later period of growth, uptake of 35S was more in the matrix of treated specimens, which was apparently not reduced due to lack of hypertrophy of cartilage cells. The mechanism of the suppressive effect of mitomycin C seems similar in vivo and in vitro.

Animals↗
PubMed1978

[Repair of damage to cells in an SPEV culture after exposure to mitomycin C].

The action of mitomycin C on a porcine embryo kidney culture (in dose of 0.5-1.5 mkg/ml in the course of 24-72 hours) is accompanied by significant changes in the ultrastructure and morphology of cells. Moreover, mitomycin C sharply inhibits DNA synthesis, mitotic activity and much more weakly suppresses protein and RNA syntheses. After a prolonged (48 hours) washing of the antibiotics only the mitochondrial ultrastructure is restored in the fresh cultural medium. DNA synthesis and mitotic activity remain suppressed, while protein and RNA syntheses increase sharply, which leads to protein accumulation in cells, and to the enlargement of nuclei, nucleoli and cells. Such changed cells are unable to keep on living and perish.

Cell Line↗
PubMed1978

The effect of mitomycin C on platelet aggregation and adenosine 3',5'-monophosphate metabolism.

The effect of Mitomycin C on aggregation, adenosine 3',5'-monophosphate (cyclic AMP) metabolism and reactions induced by thrombin was studied in rabbit platelets. Mitomycin C inhibited the platelet aggregation induced by adenosine diphosphate or thrombin. The level of radioactive cyclic AMP derived from 8-14C adenine or 8-14C adenosine increased after incubating intact platelets with Mitomycin C. Formation of radioactive adenosine triphosphate also increased though mitochondrial oxidation was not stimulated. Similar effect was observed also in rabbit liver. Mitomycin C failed to stimulate platelet adenyl cyclase but inhibited cyclic AMP phosphodiesterase in the absence of theophylline. In the platelets preincubated with Mitomycin C, thrombin-induced inhibition of adenyl cyclase, stimulation of membrane-bound cyclic AMP phosphodiesterase, and release of 250,000 dalton protein from platelet membranes were prevented. These results suggest that Mitomycin C will affect cellular membrane structure and function, and this extranuclear effect of Mitomycin C will lead to inhibition of aggregation in blood platelets.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1976

Studies related to antitumor antibiotics. Part V. Reactions of mitomycin C with DNA examined by ethidium fluorescence assay.

The cytotoxic action of the antitumor antibiotic mitomycin C occurs primarily at the level of DNA. Using highly sensitive fluorescence assays which depend on the enhancement of ethidium fluorescence only when it intercalates duplex regions of DNA, three aspects of mitomycin C action on DNA have been studied: (a) cross-linking events, (b) alkylation without necessarily cross-linking, and (c) strand breakage. Cross-linking of DNA is determined by the return of fluorescence after a heat denaturation step at alkaline pH's. Under these conditions denatured DNA gives no fluorescence. The cross-linking was independently confirmed by S1-endonuclease (EC 3.1.4.-) digestion. At relatively high concentrations of mitomycin the suppression of ethidium fluorescence enhancement was shown not to be due to depurination but rather to alkylation, as a result of losses in potential intercalation sites. A linear relationship exists between binding ratio for mitomycin and loss of fluorescence. The proportional decrease in fluorescence with pH strongly suggests that the alkylation is due to the aziridine moiety of the antibiotic under these conditions. A parallel increase in the rate and overall efficiency of covalent cross-linking of DNA with lower pH suggests that the cross-linking event, to which the primary cytotoxic action has been linked, occurs sequentially with alkylation by aziridine and then by carbamate. Mitomycin C, reduced chemically, was shown to induce single strand cleavage as well as monoaklylation and covalent cross-linking in PM2 covalently closed circular DNA. The inhibition of this cleavage by superoxide dismutase (EC 1.15.1.1) and catalase (EC 1.11.1.6), and by free radical scavengers suggests that the degradation of DNA observed to accompany the cytotoxic action of mitomycin C is largely due to the free radical O2. In contrast to the behavior of the antibiotic streptonigrin, mitomycin C does not inactivate the protective enzymes superoxide dismutase or catalase. Lastly, mitomycin C is able to cross-link DNA in the absence of reduction at pH 4. This is consistent with the postulated cross-linking mechansims.

Animals↗
PubMed1975

The induction of SV40-transformed chinese hamster and mouse kidney cells by mitomycin C.

The induction by mitomycin C (MC) of SV40 production in three lines of semi- or nonpermissive SV40-transformed cells is described. The production of virions by a line of semipermissive, virus-shedding Chinese hamster kidney cells is increased 1,000-fold by MC treatment; the proportion of infectious centers and V-antigen-containing cells is increased to a lesser degree, suggesting that both the burst per cell and the number of virus-producing cells are increased. MC treatment induces the production of small amounts of infectious DNA and virions in one line of nonpermissive mouse kidney cells, and infectious DNA apparently alone in another.

Animals↗
PubMed1976

Phase II study of profiromycin vs mitomycin-C utilizing acute intermittent schedules.

A randomized prosective study of Mitomycin-C and its N-methyl derivative, Porfiromycin, was conducted. Thirty-two patients with disseminated gastrointestinal cancer or other disseminated abdominal adenocarcinoma were treated with Mitomycin-C; 31 patients received Porfiromycin. Both drugs were given by acute intermittent bolus schedule (Mitomucin-C , 22.5 mg/M2 or Porfiromycin, 75 mg/M2 every 6--8 weeks as a single bolus i.v. injection). Eleven patients (34%) who received Mitomycin-C entered into partial remission. In 10 of the 31 patients (32%) receiving Porfiromycin, partial remission occured. Analysis by tumor type demonstrated that in the Mitomycin-C treated group responses occured in 4 of 12 patients with colorectal carcinoma, in 4 of 9 with upper GI cancers, and in 3 of 11 with ovarian cancer. Correspondingly in Porfiromycin group responses occured in 2 of 12 colorectal carcinoma patients, in 3 of 7 upper GI cancer patients, and in 5 of 12 ovarian cancer patients. Both drugs produced significant myelosuppression; however, Porfiromycin toxicity appeared more cumulative. Further clinical trial of Mitomycin in an acute intermittent bolus schedule appears justified.

Abdominal Neoplasms↗
PubMed1976

Comparative studies on the antitumor effect on intravenous administration of carbazilquinone and mitomycin-C.

Comparison between Carbazilquinone and Mitomycin-C, both of which contain aziridinyl, carbamoyloxy, and quinonyl groups, was made for their therapeutic effect upon intravenous administration. Although both agents exhibited a significant effect on plasmacytoma X5563 in C3H/He mice to a similar extent, Mitomycin-C was not as effective on lympholeukemia L-1210 and on the lung metastasis of Ehrlich carcinoma in (C57BL/6 X DBA/2)F1 (BDF1) mice as was Carbazilquinone. Possible interpretations regarding this discrepancy are discussed.

Animals↗
PubMed1978

Studies on the mechanism of action of mitomycin C.

The in vitro formation and properties of the molecular complex between mitomycin C and native DNA were examined by means of various experimental methods; the data obtained indicate that the complex is extremely weak and that the chromophoric moiety of the antibiotic is not involved in its formation. The alkylating activity of mitomycin C was also studied using 3H-mitomycin C; while monofunctional alkylation increases almost in parallel with the concentration of the antibiotic, the difunctional alkylation, causing inter-strand cross-linkages in DNA, rapidly reaches a maximum and then remains constant even when increasing the concentration of the antibiotic and monofunctional alkylation. On the basis of these results, the currently accepted molecular model of the mitomycin--DNA interaction must be revised; a new model of this interaction is presented, which is in better agreement with the properties of mitomycin C and with the latest findings on the subject.

Alkylation↗
PubMed1978

Mitomycin-C alone and in combination with infused 5-fluorouracil to the treatment of disseminated gastrointestinal carcinomas.

One hundred and thirty-two previously untreated patients with metastatic adenocarcinoma of the gastrointestinal (GI) tract were randomized to receive either a 120-hr infusion of 5-fluorouracil (5FU) with mitomycin-C or mitomycin-C alone. Superiority of the combination treatment was demonstrated with remissions in 30 out of 82 (37%) patients versus 9 out of 50 (18%) with the single drug treatment (P = 0.02). The median survial with 5FU--mitomycin-C was 29 weeks, as opposed to 20 weeks with mitomycin-C alone (P = 0.03). The combination produced significantly more severe myelotoxicity than the single drug, and jaundiced patients experienced more myelosuppression than non-jaundiced patients with both treatments.

Adenocarcinoma↗
PubMed1979

[Action of mitomycin C on the variability of Actinomyces hygroscopicus in forming a proteolytic complex of hygrolytin enzymes and the antibiotic, hygromycin B].

The lethal and mutagenic effect of mitomycin C in doses of 10 and 15 micrograms/ml on the spores and 24-hour culture of Act. hygroscopicus, strain O878 producing hygrolytin, a proteolytic enzyme and hygromycin B, an antibiotic was studied. It was found that mitomycin C had a high lethal effect on the organism. The lethal effect of the antibiotic depended on the stage of the culture development, mitomycin C dose and exposure time. The 24-hour culture was most sensitive to the effect of mitomycin in a dose of 50 micrograms/ml. Exposure to mitomycin increased the actinomycete variation with respect to the colony morphology and induction of new morphological mutations. Exposure of strain O878 to mitomycin C significantly increased the culture variation with respect to the quantitative features of production of the hygrolytin proteolytic enzyme complex and hygromycin B. The character of the strain induced variation with respect to the features studied was different which indicated the absence of correlation between them. The use of mitomycin C proved to be promising in selection of Act. hygroscopicus with a purpose of increasing the culture proteolytic and antibiotic activity.

Anti-Bacterial Agents↗
PubMed1978

Experimental results with the combination of bleomycin plus mitomycin C.

This investigation has established the following: 1. Bleomycin, in combination with mitomycin C or other quinone-containing anticancer agents, stimulated the damage to KB cells in culture. 2. In AH66 tumor-bearing rats, the simultaneous treatments of bleomycin plus mitomycin C extend the lifespan. 3. The bleomycin-induced DNA chain breakage was enhanced by the NADPH-dependent microsomal electron transport system. The enhancement was also observed at the level of isolated nuclei and cells. Vitamin K2 and mitomycin C increased breakage at the cellular level by bleomycin and NADPH. 4. Bleomycin-Cu2+ had tendency to increase the lipid peroxidation reaction by the microsomes. However, the reaction was effectively inhibited by antioxidants. 5. Bleomycin induced aldehyde formation from DNA breakage. The formation was effectively inhibited by scavenging reactions with hydralazine hydrochloride or isoniazid. The possibility of suppressing the side effect of bleomycin was discussed in relation to TBA reactive compounds.

Antibiotics, Antineoplastic↗
PubMed1977

Antitumor effect of combined use of OK-432 and yeast cell wall with mitomycin-C in mice.

Tumor-inhibitory effect of combined use of mitomycin-C and streptococcal preparation (OK-432) or yeast cell wall (YCW) was examined. Twenty-four hours after intraperitoneal inoculation of Ehrlich carcinoma cells, combination therapy was carried out and tumor growth was observed for 40 days. About one-half of mice treated with yeast cell wall at a single dose of 1 mg survived free of tumor. Mitomycin-C at a single dose of 2 microgram was not effective. However, in combination with yeast cell wall, tumor suppression was observed in 70% of the mice. This tumor-inhibitory effect was enhanced by subsequent treatment with OK-432 or yeast cell wall. When these materials were injected separately or in combination with mitomycin-C, the number of peritoneal exudate cells increased about 3 to 6 times after 3 days and these cells exhibited cytotoxic effect on tumor cells. Hemagglutinating antibody to sheep erythrocytes was hardly affected by the combination therapy.

Animals↗
PubMed1978

Electrostatic complexes of mitomycin C with nucleic acids and polyanions.

Reductively activated mitomycin C exhibits strong, non-covalent electrostatic binding to polyanions such as polyvinylsulfate and polyphosphate. The protonated C-2 amino group generated by the reduction is most likely responsible for this type of interaction. At moderate drug and salt concentrations only covalent binding to nucleic acids is observable. This is shown to be guanine-specific in DNA for the first time, as well as in synthetic polyribo- and polydeoxyribonucleotides at 10--20 times higher binding levels than previously tested. At higher mitomycin C concentration, however, strong non-covalent electrostatic binding to nucleic acids also occurs, resulting in a binding ratio up to 1 mol drug bound per mol mononucleotide, although this non-specific binding is relatively inhibited compared to polyvinylsulfate. Salts also have an inhibitory effect on the non-specific binding to nucleic acids. A series of mitomycin derivatives were compared for their binding and cross-linking abilities using DNA as substrate, with the following results: (a) the presence of a basic nitrogen . funtion at C-2 promotes binding, both covalent and electrostatic, presumably by kinetically facilitating the approach between positively charged nitrogen and DNA. (b) The aziridine ring is the major covalent binding site, indispensable for crosslinking and determines the guanine-specificity of the binding.

Anions↗
PubMed1977

Ultrastructural investigation of the effect of mitomycin C on the rat exocrine pancreas.

In order to clarify the pathophysiology of digestive disorders which are caused with anticancer agents, Mitomycin C was intravenously administrated to rats and the ultrastructure of the pancreas was studied. The alteration of acinar cells after under 4 daily administrations of 1.0 mg/Kg of Mitomycin C was not remarkable and in an early stage returned to normal structure. In above 8 daily administrations of 1.0 mg/Kg of Mitomycin C, however, pronounced degeneration of acinar cells was induced and acinar cells did not recover to the previous level, but die within one month. The ultrastructural changes induced by Mitomycin C were mainly aggregation of chromatin in the nuclei, tubularly dilatation of the rough endoplasmic reticulum, and swelling of the mitochondria. It was surmised that the biosynthesis and supply of protein such as digestive enzymes were not amply carried on; hence, the ehcmotherapy could give rise to severe digestion disorders. It appeared necessary to further study the dosage and dosage schedule of the anticancer agents, along with the necessity for taking ample care of patients presenting such disorders.

Animals↗
PubMed1978

[Effect of mitomycin C on SPEV cell cultures].

Mitomycin C (in doses of 0.5-1.5 mkg/ml during 24-72 hours) significantly changes the ultrastructure and morphology of porcine embryo kidney cells (condensation of chromatin and the mitochondrial matrix, expansion of small channels in the endoplasmatic reticulum, total hypertrophy of the nuclei and cells). In the given case, mytomycin C sharply inhibits DNA synthesis and mitotic activity, considerably more weakly reduces RNA and protein synthesis, raises the activity of lactate and alpha-glycerophosphate-dehydrogenases. The disbalance of syntheses leads to protein accumulation in the cells, and general enlargement of nuclei and cells. As the action of the antibiotics increases, the ultrastructural changes progress and lead to the destruction of a considerable part of cells in the culture.

Animals↗