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PubMed1986

Reassignment of the guanine-binding mode of reduced mitomycin C.

Mitomycin C (1) is a clinically used antitumor antibiotic that binds covalently to deoxyribonucleic acid under reductive or acidic catalysis. We have determined the structures of the adducts resulting from attack of reductively activated 1 on the dinucleoside phosphate d(GpC) to be N2-(2'' beta, 7''-diaminomitosen-1''alpha-yl)-2'-deoxyguanosine (2) and its 1'' beta-isomer (3). This represents a revision of the previously reported structures for these adducts in that the mitomycin residue is linked to the N2- rather than O6-position of 2'-deoxyguanosine. This revision is the result of applying to the mitomycin case a newly developed general method that leads to unambiguous assignment of the linkage position in complex alkylated guanosines. The method as described here takes advantage of the resolution enhancement gained by calculation of the second derivatives of absorbance Fourier transform infrared spectra. In addition, we present 1H NMR data that corroborate the assigned structures of 2 and 3 and that should serve as a useful reference for future investigations into the binding of mitomycin C to DNA. The convenient synthesis of adducts 2 and 3 from deoxyguanosine and mitomycin C reported here should facilitate such investigations as well. Furthermore, we demonstrate a useful acetylation procedure for adducts and metabolites of mitomycin C that furnishes spectroscopically superior chemical derivatives (e.g., triacetates 4 and 5, derived from acetylation of adducts 2 and 3).

Deoxyguanosine↗
PubMed1988

Reductive activation of mitomycin C.

Mitomycin C, an antitumor antibiotic, is known to require reductive activation in order to function as an alkylating agent. In this work reduction has been carried out by using radiolytically produced formate radicals that reduce mitomycin C to its semiquinone in a clean rapid one-electron reaction. The ultimate products of the reduction are cis- and trans-2,7-diamino-1-hydroxymitosene (B1 and B2) and 2,7-diaminomitosene (C). The yields of these compounds were found to be the same when the rate of reduction was varied by 11 orders of magnitude. At pH 7, one mitosene molecule is formed for every two formate radicals, while at pH 9.1, about eight mitosene molecules are formed per formate radical. The ratio of (B1 + B2)/C is less than 0.4 at pH 5.7, 1.0 at pH 7, and greater than 3.5 at pH 9.1. Observations have been made of changes in optical absorption due to the formation of the semiquinone and hydroquinone of both mitomycin C itself and 2,7-diamino-1-hydroxymitosene (B). The direct conversion of the semiquinone form of mitomycin C into the semiquinone of B proceeds slowly, if at all. The semiquinone form of B will rapidly reduce mitomycin C (k = 7.2 X 10(8) M-1 s-1). The hydroquinone of mitomycin C undergoes changes resulting in the formation of B and C. The yields of B and C depend on pH.(ABSTRACT TRUNCATED AT 250 WORDS)

Chromatography, High Pressure Liquid↗
PubMed1982

Altered physiochemical properties of the deoxyribonucleic acid-mitomycin C complex. Evidence for the conformational change in deoxyribonucleic acid.

Binding of the antibiotic mitomycin C to sonicated calf thymus DNA results in increased viscosity and an unaltered sedimentation constant of DNA. Flow dichroism measurements of the mitomycin C-DNA complex indicate that the 310-nm absorbance vector of the chromophore of the bound drug is oriented at approximately 57.2 degrees relative to the helix axis. A conclusion drawn from these results is that mitomycin C does not intercalate between base pairs, but rather, it is bound in one of the grooves. Binding of mitomycin C causes a number of changes which are DNA size dependent: (1) increased viscosity of sonicated, decreased viscosity of nonsonicate DNA; (2) unaltered sedimentation rate of sonicated, increased rate of nonsonicated DNA; (3) reduced electrophoretic mobility of nonsonicated DNA; (4) electron microscopic appearance of sonicated DNA-mitomycin complexes which is similar to that of control, while nonsonicated DNA complexes which display highly coiled, looped structures not seen in control nonsonicated DNA. These size-dependent effects are interpreted as indicative of conformational distortion of DNA at rare intervals, caused by a minor fraction of total bound mitomycin. The parallel used of sonicated and nonsonicated DNA as probes for certain effects of drug binding may be useful for detecting this type of phenomenon in general.

Animals↗
PubMed1990

A comparative study of isolated liver perfusion versus hepatic artery infusion with mitomycin C in rats.

Systemic toxicity is usually the dose-limiting factor in cancer chemotherapy. Regional chemotherapy is therefore an attractive strategy in the treatment of liver metastasis. Two ways of regional chemotherapy, hepatic artery infusion (HAI) and isolated liver perfusion (ILP), were compared investigating the difference in toxicity with tissue and biofluid concentrations of mitomycin C (MMC). In wistar derived WAG rats the maximally tolerated dose of mitomycin C via HAI was 1.2 mg kg-1. Body weight measurements after HAI with doses higher than 1.2 mg kg-1 suggest both an acute and delayed toxic effect of mitomycin C since the time weight curves were triphasic: a rapid weight loss, a steady state and a second fall in weight phase. These rats died due to systemic toxicity. ILP with 4.8 mg kg-1 was associated with no signs of systemic toxicity and only transient mild hepatotoxicity. ILP with 6.0 mg kg-1 was fatal mainly due to hepatic toxicity. The four times higher maximally tolerated dose in ILP resulted in a 4-5 times higher peak concentration of mitomycin C in liver tissue, while the plasma concentration remained significantly lower than in the HAI treated rats. In the tumour tissue a 500% higher concentration of mitomycin C was measured in the ILP with 4.8 mg kg-1 than in HAI with 1.2 mg kg-1 treated rats. We demonstrated that when mitomycin C was administered by ILP a 400% higher dose could be safely administered and resulted in a five times higher tumour tissue concentration. In view of the steep dose-response curve of this alkylating agent this opens new perspectives for the treatment of liver metastasis.

Animals↗
PubMed1991

Effectiveness of isolated liver perfusion with mitomycin C in the treatment of liver tumours of rat colorectal cancer.

Dose limiting systemic toxicity prevents sufficient exploitation of the steep dose response relationship of most anticancer agents. In our rat liver tumour model (the CC531 colorectal carcinoma), isolated liver perfusion allows administration of higher doses of mitomycin C than hepatic artery infusion, while systemic toxicity remains minimal. To determine the temporal pattern of mitomycin C induced cytokinetic changes, we analysed flow cytometric DNA histograms of CC531 liver tumours from rats treated with high dose mitomycin C (3.2 mg kg-1) via hepatic artery infusion and sacrificed at different time intervals after treatment. Between 12 and 36 h after treatment, the fraction of cells in late S and G2/M phase had markedly increased. The effects of administration of the respective maximally tolerated doses of mitomycin C in isolated liver perfusion and via hepatic artery infusion on progression of tumour cells through the cell cycle and on gross tumour growth were compared. Isolated liver perfusion with mitomycin C resulted in a significant increase in the proportion of cells in mid and late S, and in some accumulation of cells in early S and G2/M phase at 24 and 48 h after treatment. In contrast, after hepatic artery infusion a significant increase of the fraction of cells in G2/M phase was observed at 24 h after treatment. Monitoring tumour growth after isolated liver perfusion five out of seven rats showed a complete tumour remission, while after hepatic artery infusion only a minimal growth delay was detected. This study demonstrates that isolated liver perfusion in the rat CC531 liver tumour model allows the administration of a well-tolerated dose of mitomycin C being high enough to induce a marked DNA synthesis inhibition and even complete tumour remission.

Animals↗
PubMed1986

Reaction of DNA with chemically or enzymatically activated mitomycin C: isolation and structure of the major covalent adduct.

The antitumor antibiotic mitomycin C is shown to form a covalent complex with calf thymus DNA under anaerobic conditions in the presence of either NADPH cytochrome c reductase/NADPH, xanthine oxidase/NADH, or the chemical reducing system H2/PtO2. Digestion of the complex with DNase I/snake venom diesterase/alkaline phosphatase yields a single mitomycin deoxyguanosine adduct as the major DNA alkylation product, identified as N2-(2'' beta,7''-diaminomitosen-1'' alpha-yl) 2'-deoxyguanosine (Structure 2). Two minor adducts, 2-5% each of the total adduct pool, are isolated and identified as the 1'' beta stereoisomer of 2 (Structure 3), and 10''-decarbamoyl-2 (Structure 7). The same results were obtained with M13 DNA and poly(dG-dC).poly(dG-dC); however, in the latter case, a minor adduct apparently possessing two deoxyguanosine and one mitomycin unit is isolated. Digestion of the covalent mitomycin-calf thymus DNA complex with nuclease P1 yields four dinucleotide adducts, all of which consist of 2 linked at its 3' end to each of the four possible 5' nucleotides (A, T, G, and C). Upon treatment of each dinucleotide adduct with snake venom diesterase/alkaline phosphatase, 2 is released along with the corresponding free nucleoside. In apparent conflict with the present results, previous reports from another laboratory have indicated that modification of calf thymus DNA by mitomycin C under conditions identical to those described here result in the isolation of three mitomycin C mononucleotide adducts possessing linkages of the drug to N2 and O6 of guanine and N6 of adenine. Evidence is shown suggesting that the latter adducts are actually three of the above four dinucleotide derivatives of 2 obtained independently by us and, thus, all of them in fact possess an identical N2-mitosenylguanine adduct moiety. Model-building studies indicate an excellent fit of the guanine N2-linked drug molecule inside the minor groove of B-DNA with no appreciable distortion of the DNA structure.

Alkaline Phosphatase↗
PubMed1990

Histopathological effects and recovery rate of rat bladders following intravesical instillation of thiotepa, doxorubicin and mitomycin C.

A study was made of the local reactions and systemic effects induced by intravesical instillations of thiotepa, doxorubicin and mitomycin C in rats. The control group received normal saline. In the 1-dose short-term experiments, rats treated with doxorubicin and mitomycin C had a high incidence of chemical reactions, including congestion of the mucosa with methylene blue stain, increased bladder weight with oedematous changes either in the mucosa (doxorubian) or the muscle layer (mitomycin C), and infiltration of polymorphonuclear cells 3 days after instillation. These local changes disappeared within 10 days. In long-term experiments with weekly instillations of chemotherapeutic drugs, the rats showed no significant change in weight, methylene blue staining or mucosal congestion. A high percentage of pyuria and microscopic haematuria with submucosal/muscular fibrosis was noted in rats receiving doxorubicin or mitomycin C. A severe dysplastic change in the urothelium was noted in rats treated with mitomycin C. These results suggest that careful follow-up is required in patients receiving intravesical doxorubicin or mitomycin C because of possible severe side effects in the bladder.

Administration, Intravesical↗
PubMed1982

Rescue of mitomycin C- or psoralen-inactivated Micrococcus radiodurans by additional exposure to radiation or alkylating agents.

The processing of damaged DNA was altered in a mitomycin C-sensitive mutant (mtcA) of Micrococcus radiodurans. Even though the mutant retained resistance to 254-nm UV radiation, it did not, in contrast to the wild-type strain, show any excessive DNA degradation or cell death when incubated with chloramphenicol after sublethal doses of either UV light or mitomycin C. The results suggest the constitutive synthesis of an enzyme system responsible for wild-type proficiency in the repair of mitomycin C-induced damage. An alternative system able to repair damage caused by mitomycin C was demonstrated in the mtcA background. In this strain, additional damage inflicted upon the cellular DNA effected a massive rescue of cells previously inactivated by mitomycin C. Rescue was provoked by ionizing radiation, by UV light, or by simple alkylating agents. Cells treated with psoralen plus near-UV radiation could be rescued only when inactivation was due primarily to psoralen-DNA interstrand cross-links rather than to monoadducts. The rescue of inactivated cells was prevented in the presence of chloramphenicol. These results can be interpreted most readily in terms of an alternative repair system able to overcome DNA interstrand cross-links produced by mitomycin C or psoralen plus near-UV light, but induced only by the more abundant number of damages produced by radiation or simple alkylating agents.

Alkylating Agents↗
PubMed1963

INHIBITION OF MICROBIAL GROWTH AND SEPARATION BY D-SERINE, VANCOMYCIN, AND MITOMYCIN C.

Durham, Norman N. (Oklahoma State University, Stillwater). Inhibition of microbial growth and separation by d-serine, vancomycin, and mitomycin C. J. Bacteriol. 86:380-386. 1963.-A study was made of the growth and separation inhibition of Pseudomonas fluorescens by vancomycin and mitomycin C and of a Flavobacterium sp. sensitive to mitomycin C and d-serine. Aberrant morphological forms (primarily "boat-shaped" cells and "chain-like" filaments) were observed during growth of the sensitive organism in the presence of the inhibitors. Reversal studies indicated that Mg(++), and to a lesser extent Mn(++), partially reversed vancomycin and mitomycin C growth inhibition during the early stages of growth but did not influence d-serine inhibition. Selected metabolites also showed a tendency to partially reverse mitomycin C and vancomycin inhibition of growth during the initial growth phase, and the differences in reversal trends suggested that d-serine, vancomycin, and mitomycin C produce metabolic lesions at different sites in the cell with respect to growth. Cultivation of the sensitive organism in low concentrations of the inhibitors resulted in a structurally fragile population, indicating formation of a defective cell structure. Mg(++) partially reversed the vancomycin inhibition of separation in these organisms. None of the other metals or metabolites, either singly or in varied combinations, was able to reverse inhibition of separation by the various inhibitors.

Flavobacterium↗
PubMed1987

Mitomycin C pharmacokinetics in patients with recurrent or metastatic colorectal carcinoma.

The pharmacokinetics of mitomycin C as a single agent have been determined in 25 treatment courses given to 18 patients with recurrent or metastatic colorectal carcinoma using a high performance liquid chromatography (HPLC) assay to analyze plasma and urine samples. The plasma pharmacokinetics conformed to a two-compartment linear model in 21 of 25 courses monitored with a mean t1/2 lambda 1 of 9.8 +/- 1.2 (SEM) min and mean t1/2 lambda z of 64.1 +/- 8.9 (SEM) min. The large variation observed in t1/2 lambda z was not related to dose or treatment, but an interaction of these two factors approached significance (p = 0.057). Renal excretion in the 12 courses in which it was determined averaged only 2.3% of the total administered dose during the first 4 h monitored and no mitomycin C metabolites were detected in plasma or urine by the HPLC technique used. The most common toxicity, thrombocytopenia, did not correlate with t1/2 lambda z or the area under the curve. This may be due to a failure to monitor active metabolites of mitomycin C; other factors besides plasma drug concentrations that mediate toxicity towards marrow elements; or the small number of courses associated with thrombocytopenia (less than 100,000/mm3). Our study indicates that an interaction of drug dose and treatment course may be associated with increasing t1/2 lambda z; the renal clearance contributes a small component of mitomycin C elimination; metabolites of mitomycin C cannot be detected by the present HPLC technique; and routine monitoring of mitomycin C using present methods cannot be recommended for clinical use to predict toxicity.

Aged↗
PubMed1983

Treatment of advanced breast cancer with mitomycin C combined with vinblastine or vindesine.

Mitomycin C together with either vindesine or vinblastine was given to 48 patients with previously treated advanced breast cancer. Thirteen (35%) of the 37 evaluable patients had a complete (one patient) or partial (12 patients) response. Overall median duration of response was 189 days (range, 90-700 days). Fifteen patients received mitomycin C and vindesine with six responses (40%) and a median response duration of 247 days (range, 162-700 days). Twenty-two patients received mitomycin C and vinblastine with seven responses (32%) and median response duration of 164 days (range, 90-330 days). Response duration for patients treated with mitomycin C plus vindesine was longer than that associated with mitomycin C plus vinblastine (p = 0.09). Significant toxicity included myelosuppression and neurologic symptoms, but was uncommon (less than 10% of patients). Therefore, the combination of mitomycin C and a vinca alkaloid appears to be useful in far-advanced refractory breast cancer.

Adult↗
PubMed1989

Pharmacokinetics of intra-arterial mitomycin C with or without degradable starch microspheres (DSM) in the treatment of non-resectable liver cancer.

The effects of degradable starch microspheres (DSM) on mitomycin C pharmacokinetics and bone marrow toxicity were studied in a phase II multicenter study. Sixty-three patients with non-resectable primary or secondary liver cancer were randomized to receive either i.a. mitomycin C 15 mg/m2 first, followed 5 weeks later by mitomycin C 15 mg/m2 plus DSM 360 mg administered into the hepatic artery (group I) or the same treatments in the opposite sequence (group II). In 36 out of 47 patients who received at least 2 treatments, peripheral venous blood samples were analyzed for mitomycin C pharmacokinetics on a minimum of 2 paired courses. In all patients, the area under the concentration time curve (AUC) was significantly lower when the drug was co-administrated with DSM, but the terminal half-life (t1/2) of mitomycin C was unchanged. In group I the addition of DSM resulted in a significantly lowered AUC, but not in group II. The discrepancy between the 2 groups is probably due to differences in DSM-induced intra-hepatic shunting. The addition of DSM resulted in significantly higher platelet nadir values, but unchanged white blood cell count nadir value. In conclusion, DSM reduce the systemic exposure of mitomycin C and seem to lessen the haematologic toxicity judged from a less pronounced decrease in platelets.

Adult↗
PubMed1991

Cytotoxicity and DNA crosslinks produced by mitomycin analogs in aerobic and hypoxic EMT6 cells.

Several mitomycin antibiotics were evaluated for their capacities to kill EMT6 tumor cells and to produce DNA crosslinks under conditions of oxygenation and hypoxia. The agents examined included mitomycin C, porfiromycin, and the 7-aminomethyl dithioacetal derivative of mitomycin C (BMY-43324), all of which caused greater kill of hypoxic cells than of their oxygenated counterparts; the N,N'-dimethylaminomethylene derivative of mitomycin C (BMY-25282), which was considerably more cytotoxic under oxygenated conditions than in hypoxia; and the N,N'-dimethylaminomethylene derivative of porfiromycin (BL-6783), which was equal in its toxicity to hypoxic and oxygenated cells. All of these agents produced DNA crosslinks in EMT6 cells, as measured by alkaline elution. The number of crosslinks required to produce a given amount of cell kill was similar, regardless of the mitomycin employed or the degree of oxygenation, suggesting that the crosslinking of DNA was a major lesion in the cytodestructive action of the mitomycins.

Aerobiosis↗
PubMed1990

Affinity of intraperitoneally injected activated carbon particles adsorbing mitomycin C to tumor surface of Yoshida sarcoma.

A new dosage form of mitomycin C (MMC-CH) comprising 0.75 mg/ml of activated carbon particles adsorbing mitomycin C at 124 micrograms/mg and 7 micrograms/ml of mitomycin C in a free state was injected intraperitoneally to male rats of Donryu strain transplanted intraperitoneally with 10(7) cells/rat of Yoshida sarcoma 4 days before injection. The rats were subjected to autopsy within 60 min after injection. MMC-CH adhered selectively to the tumor surface of Yoshida sarcoma growing intraperitoneally rather than to the surface of organs such as small intestines which the surface cancer did not affect. Within 120 min after injection, mitomycin C concentration in the tissue samples was bioassayed. Intraperitoneally injected MMC-CH distributed high levels of mitomycin C to the tumor rather than to the unaffected organ located intraperitoneally. Animals killed by cancer after the treatment of MMC-CH were autopsied. Histological effects of MMC-CH were studied microscopically. Mitomycin C adsorbed on activated carbon particles induced degenerative changes in the tissues of tumors to which the activated carbon particles had adhered.

Adsorption↗
PubMed1983

Activity of mitomycin C for aerobic and hypoxic cells in vitro and in vivo.

We have observed the selective toxicity of mitomycin C toward hypoxic as compared to aerobic cells in vitro for three established cell lines (Chinese hamster ovary, Chinese hamster V-79, and human HeLa) and for cells from the transplantable KHT murine tumor. The magnitude of the selective toxicity was cell line dependent. We have studied the in vivo effects of mitomycin C against aerobic and hypoxic cells of two transplantable murine tumors: the KHT fibrosarcoma and the 16/C mammary carcinoma. Either mitomycin C was given with radiation to kill most of the aerobic cells, or it was given alone. Endpoints of response were cell survival assessed by lung colony assay for the KHT tumor, and growth delay for the 16/C tumor. In some experiments, mitomycin C appeared more effective when used with radiation than when used alone, but the results of combined treatment fell just within the range of additivity as defined by isobologram analysis. The effects of combined treatment were independent of the order in which drug and radiation were given. Mitomycin C was also used in combination with Adriamycin to treat the 16/C tumor, since we have found previously that Adriamycin spares hypoxic cells in this tumor. In three of four experiments, combined drug effects were slightly greater than predicted by an additive relationship. We conclude that mitomycin C is active against hypoxic cells in two murine tumors, but that it has at most minor specificity for hypoxic as compared to aerobic cells in vivo.

Aerobiosis↗
PubMed1993

Long-term effects of mitomycin on filtering blebs. Lack of fibrovascular proliferative response following severe inflammation.

BACKGROUND AND OBJECTIVE: The use of antimetabolites, such as fluorouracil and mitomycin, enhances the success rate of filtering surgery, especially in eyes at high risk for failure, and increases the likelihood of a thin, avascular filtering bleb. In addition, mitomycin may cause long-term inhibition of the fibroblast's ability to proliferate in the conjunctiva and Tenon's capsule. Preoperative and postoperative inflammation frequently contributes to scarring of filtering blebs. The purpose of this study is to evaluate the effect of intraoperative mitomycin use on the survival of filtering blebs after severe inflammation. DESIGN: We retrospectively studied three eyes that had undergone trabeculectomy with intraoperative mitomycin. Two eyes had concomitant intraocular lens implantation. All three eyes had blebs that functioned well postoperatively. PATIENTS: These eyes sustained episodes of intense inflammation in the form of herpes zoster ophthalmicus, endophthalmitis, or purulent infection of the bleb postoperatively. RESULTS: Following treatment of the inflammation, no change in the appearance or function of the bleb could be detected. CONCLUSION: Either the indirect effect of mitomycin in producing a thin, avascular bleb or a long-term effect of mitomycin on the ability of conjunctival and Tenon's capsule fibroblasts to proliferate may have contributed to bleb survival.

Aged↗
PubMed1995

Mitomycin C suppresses aqueous human flow in cynomolgus monkeys.

OBJECTIVE: To determine whether mitomycin C suppresses aqueous humor formation in cynomolgus monkeys. METHODS: Three monkeys received subconjunctival injections (50 microL) in four quadrants bilaterally, one eye receiving mitomycin C (0.5 mg/mL) and the other receiving distilled water. Seven monkeys underwent 360 degrees conjunctival peritomy bilaterally and episcleral application of mitomycin C-soaked (0.5 mg/mL) cellulose sponges for 5 minutes in all four quadrants unilaterally. Aqueous humor flow was measured fluorophotometrically 1 and 3 days, and 1, 2, and 4 weeks after subconjunctival injection; and 3 days and 1, 2, 3, and 4 weeks after episcleral application. RESULTS: There was no change in aqueous flow in either eye and no difference between eyes following subconjunctival injection. Aqueous flow was reduced by 8% +/- 7% (mean +/- SEM), 20% +/- 3% (P < .01), 9% +/- 10%, and 0% +/- 4% compared with contralateral controls 1, 2, 3, and 4 weeks, respectively, after episcleral application of mitomycin C. CONCLUSIONS: Episcleral application of mitomycin C can produce at least a modest short-term reduction of aqueous humor flow in primates. Reduced aqueous flow might contribute to early postoperative hypotony following trabeculectomy with mitomycin C.

Animals↗
PubMed1996

Use of mitomycin C in the treatment of conjunctival primary acquired melanosis with atypia.

A patient who had primary acquired melanosis with marked atypia shown on histological studies received topical 0.02% mitomycin C for 2 weeks and 0.04% mitomycin C for an additional 2 weeks. Conjunctival biopsy specimens were obtained to evaluate the efficacy of the treatment. After the first course of mitomycin C administration, some decrease of conjunctival pigmentation was seen, and histological studies disclosed a lower degree of atypia. After the second application of mitomycin C, the pigmentation disappeared except for one small spot that contained only a few typical melanocytes on histological study. The clinical findings did not change during 7 months of follow-up. No adverse reactions to topical mitomycin C occurred except for mild conjunctival hyperemia at the end of the courses of treatment. Administration of topical mitomycin C may be an effective medical treatment for primary acquired melanosis with atypia.

Administration, Topical↗