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PubMed1993

Cytosine methylation enhances mitomycin C cross-linking.

Mitomycin C (MC) is a powerful antitumor agent that targets the DNA sequence CpG. Because it is likely that this dinucleotide will contain 5-methylcytosine in vivo, we have compared the cross-linking efficiency of MC for DNA containing either 5-methylcytosine or normal cytosine embedded in random-sequence DNA oligomers. We have found that mitomycin C displays a small but significant preference for methylated DNA. Recognition of an abnormal methylation pattern in the DNA of transformed cells may therefore be one mechanism by which MC exerts its chemotherapeutic effects.

5-Methylcytosine↗
PubMed1993

Structure-activity relationships for mitomycins. Application of the distance and charge analysis method.

Molecular orbital calculations based on coordinates from X-ray analysis have been performed for a set of 24 mitomycins, of which eight compounds have not been isolated so far. To prioritize the order of synthesis of these missing compounds, a new method named DISCA (distance and charge analysis) has been developed. DISCA screens correlations between spatial distribution of charge in molecules and their biological activity. The spatial distribution of charge is represented by several indexes in DISCA. LD50 and ED50 were used as measures of biological activity. DISCA has successfully extracted indexes which have significantly high correlation coefficients. The indexes with the highest correlation coefficient were common to both LD50 and ED50. By use of the correlation functions with high correlation coefficients DISCA has predicted that 9-epi-1a-N-demethylmitomycin D should have the best ED50 and a modest LD50 among the missing mitomycins.

Mitomycins↗
PubMed1989

Mitomycin C analogues with a substituted hydrazine at position 7. Synthesis, spectral properties, and biological activity.

A select number of mitomycin C derivatives with a substituted hydrazine group at position 7 were synthesized and tested for antineoplastic activity by using an in vivo test with murine P388 leukemia. Several of the adducts displayed activity comparable to that of mitomycin C. The X-ray-determined crystal structure of one of the derivatives (3f) is reported.

Animals↗
PubMed1981

Synthesis and antineoplastic activity of mitosene analogues of the mitomycins.

A series of 1-substituted mitosene analogues of the mitomycin antitumor antibiotics was prepared by total synthesis and screened for activity against P388 leukemia in mice. In general, analogues with moderately good leaving groups (mostly esters) at the 1 position were active, whereas analogues without such substituents were inactive or barely active. These results lend support to the idea that mitosenes with leaving groups at position 1 are capable of bifunctional alkylation of DNA in a manner similar to that of mitomycin C. The most active mitosenes were equal in potency (minimum effective dose) to a corresponding aziridinomitosene, but they were less effective in prolonging life span.

Animals↗
PubMed2001

Reductive activation of mitomycin A by thiols.

[reaction: see text]. Mitomycin C is unchanged upon exposure to thiols under physiological conditions. Its more toxic variant, mitomycin A (MA), undergoes elimination of methanol to give a variety of mitosene derivatives, diagnostic of its activation to a reactive electrophile. Evidence is presented for a novel reductive mechanism, characterized by the transient addition of a thiol to the quinone of MA, followed by intramolecular electron transfer, leading to reduced quinone and oxidized thiol.

Methanol↗
PubMed1998

The major mitomycin C-DNA monoadduct is cytotoxic but not mutagenic in Escherichia coli.

To determine the mutagenic and genotoxic properties of the major guanine N2-adduct formed by the antitumor drug mitomycin C, we have synthesized a decanucleotide, d(TTACG[MC]TATCT), containing the adduct, which was inserted into a gapped bacteriophage M13 genome. Analysis of the constructed genome indicated that 41% ligation of the adducted 10-mer occurred on both sides of the gap, whereas the control 10-mer ligated with 34% efficiency. After transfection of the adducted single-stranded M13 DNA into Escherichia coli, the adduct was found to be highly genotoxic. Viability of the adducted genome in a repair-competent strain was only 7%, which increased to 12% and 15% upon induction of SOS by irradiating the cells with 254-nm light at 20 and 50 J/m2, respectively. Even lower viability of 2%, 4.6%, and 0.2% was observed in uvrA, uvrB, and uvrC strains, respectively, which increased up to 10-fold with SOS. An examination of the surviving phage populations revealed that the adduct was not detectably mutagenic. No mutants from the repair-proficient strain were detected after analysis of more than 2500 progeny phage. Only 0.2% of the survivors were mutants in the uvrA strain. It is uncertain, however, if they were induced by the adduct, since all the mutants showed untargeted mutations. We conclude that the major guanine N2-adduct formed by mitomycin C is cytotoxic but not appreciably mutagenic in E. coli.

Bacteriophages↗
PubMed1997

A phase II study of mitomycin C and oral etoposide for advanced adenocarcinoma of the upper gastrointestinal tract.

BACKGROUND: Mitomycin C and etoposide have both demonstrated activity against gastric carcinoma. Etoposide is a topoisomerase II inhibitor with evidence for phase-specific and schedule-dependent activity. PATIENTS AND METHOD: Twenty-eight consecutive patients with advanced upper gastrointestinal adenocarcinoma were treated with intravenous (i.v.) bolus mitomycin C 6 mg/m2 on day 1 every 21 days to a maximum of four courses. Oral etoposide capsules 50 mg b.i.d. (or 35 mg b.i.d. liquid) were administered days 1 to 10 extending to 14 days in subsequent courses if absolute neutrophil count > 1.5 x 10(9)/l on day 14 of first course, for up to six courses. RESULTS: Twenty-six patients were assessed for response of whom 12 had measurable disease and 14 evaluable disease. Four patients had a documented response (one complete remission, three partial remissions) with an objective response rate of 15% (95% confidence interval (95% CI) 4%-35%). Eight patients had stable disease and 14 progressive disease. The median survival was six months. The schedule was well tolerated with no treatment-related deaths. Nine patients experienced leucopenia (seven grade II and two grade III). Nausea and vomiting (eight grade II, one grade III), fatigue (eight grade II, two grade III) and anaemia (seven grade II, two grade III) were the predominant toxicities. CONCLUSION: This out-patient schedule is well tolerated and shows modest activity in the treatment of advanced upper gastrointestinal adenocarcinoma. Further studies using protracted schedules of etoposide both orally and as infusional treatment should be developed.

Adenocarcinoma↗
PubMed2001

Randomized phase III trial of bleomycin, vindesine, mitomycin-C, and cisplatin (BEMP) versus cisplatin (P) in disseminated squamous-cell carcinoma of the uterine cervix: an EORTC Gynecological Cancer Cooperative Group study.

PURPOSE: Three previous mitomycin-cisplatin-based chemotherapy trials conducted within the EORTC Gynecological Cancer Cooperative Group (GCCG) in patients with disseminated squamous-cell carcinoma of the uterine cervix (SCCUC) suggested that with such regimens a higher overall response rate and a higher complete response rate could be obtained compared to what might have been expected from cisplatin alone. In that respect the combination of bleomycin, vindesine (Eldesine), mitomycin C and cisplatin (BEMP) was the most promising. In the present study BEMP has been compared with the best single agent, cisplatin (P) in the expectation that improved response rates might translate into a better survival. PATIENTS AND METHODS: Eligible patients were those with SCCUC and disseminated measurable disease outside previously irradiated areas, aged < or = 75 years, with a WHO performance status < or = 2 and adequate bone marrow, renal, hepatic and pulmonary function, who gave consent according to regulations followed in individual institutions. Patients were randomized to BEMP: E 3 mg/m2 day 1, P 50 mg/m2 day 1, B 15 mg (24-hour infusion) day 2-4 and M 8 mg/m2 (at alternate cycles), or P 50 mg/m2. The first four cycles were given every 3 weeks (induction phase). Subsequent cycles were given every four weeks (maintenance phase), during which B was deleted from BEMP (MEP). Patients failing on P could be treated with BEM. Of the 287 patients entered, 235 were eligible and 201 evaluable for response. RESULTS: BEMP induced a significantly higher response rate than P (42% vs. 25%, P = 0.006). There was no difference in complete response rate (11% vs. 7%). BEMP was significantly more toxic than P (+/- BEM), both with respect to hematologic and nonhematologic toxicities. After a median follow-up of 6.1 years, survival curves were not significantly different. Median progression-free survival and overall survival were 5.3 and 10.1 months with BEMP and 4.5 and 9.3 months with P (+/- BEM), respectively. In a multivariate analysis of prognostic factors for survival, a lower age (P = 0.003), a lower performance status (P = 0.0001) and a short (<1 year) interval since diagnosis (P = 0.0152) were all associated with an increased risk of dying. For progression-free survival, lower age, prior radiotherapy, locoregional involvement and no prior surgery were associated with a high risk. Treatment with BEMP or P had no significant impact on survival, but for progression-free survival there was a trend in favor of BEMP (P = 0.0893). Adjusting for prognostic factors did not change the effect of treatment. CONCLUSIONS: Combination chemotherapy with BEMP produces more toxicity and more responses compared with cisplatin alone in patients with disseminated SCCUC, but this does not translate into a better survival. Therefore, in the palliative setting single-agent cisplatin should remain the standard therapy for these patients.

Adult↗
PubMed2002

Effect of mitomycin C on distribution of chromatid exchanges and their dose dependency in resting human lymphocytes.

Cells distribution by the number of chromatid exchanges induced by mitomycin C corresponds to geometric distribution. The dependences of the number of chromatid exchanges and the number of fragments on the dose of the mutagen are described by exponential and linear curves, respectively. Quantitative regularities of mitomycin C-induced chromosome aberrations correspond to those of "monocentric" mutagens.

Alkylating Agents↗
PubMed1998

Intraoperative mitomycin C and the corneal endothelium.

PURPOSE: Mitomycin-C (MMC) is a useful adjunct to high risk glaucoma surgery. No clinical data regarding the deleterious effect of mitomycin-C on the corneal endothelial cells are available. METHODS: Thirty eyes of 28 adult patients with high risk glaucomas were randomized to three groups. Group-I underwent a trabeculectomy alone, Group II, trabeculectomy with intraoperative 0.2mg/ml MMC and Group III, trabeculectomy with intraoperative 0.4mg/ml MMC. Preoperative and 3-month postoperative corneal endothelial cell counts were analysed. RESULTS: The percentage cell loss in Group I was 3.73+/-2.73%, in Group II 13.90+/-4.69% and in Group III 14.52+/-7.8%. Statistical analysis revealed a significant difference in cell loss between Group I and Group II and Group I and Group III, but not between Group II and Group III. CONCLUSION: There is a significant loss of corneal endothelial cells three months after trabeculectomy with adjunctive MMC.

Adult↗
PubMed2000

Diffuse retinal hemorrhages (ocular decompression syndrome) after trabeculectomy with mitomycin C for neovascular glaucoma.

PURPOSE: To describe a case of ocular decompression syndrome in a patient after trabeculectomy with mitomycin C for neovascular glaucoma. RESULTS: Diffuse retinal hemorrhages developed in the posterior pole of a patient with neovascular glaucoma after he underwent trabeculectomy with mitomycin C. The hemorrhages persisted for less than 9 months. CONCLUSIONS: Acute decompression of the eye in patients with high intraocular pressure can lead to the development of posterior pole hemorrhages. The course of this rare syndrome is relatively benign.

Aged↗
PubMed1981

Induction of 8-azaguanine resistance and sister chromatid exchange in human lymphocytes exposed to mitomycin C and X rays in vitro.

Indirect evidence implies that 8-azaguanine-resistant (AGr) lymphocytes in human peripheral blood are mutants associated with the loss of the hypoxanthine-guanine phosphoribosyltransferase (HPRT) locus on the active X chromosome, the mutation frequency increasing linearly with age. AGr variants are readily induced in lymphocytes exposed to mitomycin C in vitro, their incidence correlating with induced sister chromatid exchanges (SCEs). Although SCE events and the development of an AGr phenotype may reflect a common type of DNA damage, mitomycin C-induced Agr variants are not mutants but are suggested to be cells having a transcriptional block at the HPRT locus. AGr variants are also readily induced by X rays in vitro, their incidence correlates closely with the incidence of aberrations induced in the X chromosome and they are considered to have a mutational origin.

Age Factors↗
PubMed1994

Phase I study of mitozantrone, methotrexate and mitomycin with granulocyte colony-stimulating factor (filgrastim) in patients with advanced breast cancer.

The combination of mitozantrone, methotrexate and mitomycin (3M) gives a response rate of around 50% in patients with advanced breast cancer. The predominant toxicity is haematological. In this study, previously untreated patients were given 3M with increasing doses of mitozantrone (7-14 mg m-2) with recombinant human granulocyte colony-stimulating factor (metHuG-CSF) (filgrastim) to prevent marrow toxicity. Doses administered were 7 mg m-2 mitomycin i.v. 6 weekly, methotrexate i.v. 35 mg m-2 (maximum 50 mg) 3 weekly and mitozantrone i.v. 3 weekly as follows: 7 mg m-2, six patients (group 1); 10 mg m-2, six patients (group 2); 12 mg m-2, six patients (group 3); 14 mg m-2, six patients (group 4); all on day 1 for six cycles at the assigned dose. All patients received filgrastim (Amgen 0.3 mg ml-1) at a dose of 5 micrograms kg-1 subcutaneously daily on days 4-17 of each cycle. All treatment was given on an out-patient basis. A total of 24 patients were entered into the study. The median age was 63 years (range 48-75). ECOG performance status was 0 in ten, 1 in 11 patients and 2 in three patients. Locoregional disease alone was present in seven patients. The remainder had one or more sites of metastases. The actual dose administered to the 24 patients was as follows. The six patients in group 1 all completed six courses of treatment as per protocol. In group 2, three patients completed six courses, two stopped because of toxicity after one and four courses and one had progressive disease after one course. In group 3, three patients completed and three stopped early because of progressive disease. In group 4, two patients completed, one progressed after four courses and three responding patients stopped treatment because of toxicity. The maximum tolerated dose of mitozantrone in the 3M combination was 12 mg m-2. The use of filgrastim with increasing doses of chemotherapy prevents neutropenia, but other toxicities, namely thrombocytopenia and lethargy, then become dose limiting.

Aged↗
PubMed2002

Irinotecan, cisplatin and mitomycin in inoperable gastro-oesophageal and pancreatic cancers - a new active regimen.

Irinotecan, mitomycin and cisplatin all demonstrate activity in gastro-oesophageal cancers. This novel combination was administered to outpatients with previously untreated inoperable gastro-oesophageal or pancreatic cancer, in a 28-day cycle. A total of 26 out of 31 patients with gastro-oesophageal cancer and 12 out of 14 patients with pancreatic cancer have been treated with this combination, and were evaluable for response. The overall response rates for patients with gastro-oesophageal cancer was 42%, with a median survival of 9.5 months. In patients with pancreatic cancer, the overall response rate was 42% with a median survival of 8 months. There was a statistically significant increase in survival between those patients who achieved a stable disease response and those who achieved either a partial response or complete response. The toxicity profiles for both cancers were virtually identical. There were five treatment-related deaths, and a high admission rate (42%). Thus irinotecan, mitomycin and cisplatin is a new combination with activity in inoperable upper gastro-oesophageal cancers, but with a high toxicity profile. Future developments include reducing the dose of irinotecan and number of cycles of therapy to four.

Adenocarcinoma↗
PubMed2005

Mitomycin C, vinblastine and cisplatin (MVP): an active and well-tolerated salvage regimen for advanced breast cancer.

This phase II study assessed the clinical efficacy and tolerability of a combination of mitomycin C, vinblastine and cisplatin in patients with metastatic breast cancer (MBC) previously treated with chemotherapy. A total of 87 patients with MBC, most of whom had been exposed to anthracyclines (92%) and/or taxanes (29%) in the adjuvant and/or metastatic setting, were treated with mitomycin C (8 mg m(-2) day 1 cycles 1, 2, 4 and 6), vinblastine (6 mg m(-2) day 1) and cisplatin (50 mg m(-2) day 1) repeated each 21 days for a maximum of six cycles. The overall response rate (ORR) was 32% (95% CI: 22-42%) with 31% partial response (PR) and one complete response (CR). Stable disease (SD) rate was 21% (95% CI: 12-29%). There was no statistically significant difference in the ORR when MVP was given as the first-line treatment for MBC vs second or subsequent line (38 vs 30%, P=0.6), or between patients with an early (<6 months) vs late (>6 months) relapse post-anthracyclines (30 vs 52%, P=0.3). Toxicity profile was mild. This platinum-based chemotherapy is an effective, well-tolerated and low-cost regimen for patients with MBC, including those pretreated with anthracyclines.

Adult↗
PubMed1999

Induction with mitomycin C, doxorubicin, cisplatin and maintenance with weekly 5-fluorouracil, leucovorin for treatment of metastatic nasopharyngeal carcinoma: a phase II study.

The combination of cisplatin and 5-fluorouracil (5-FU) (PF) is the most popular regimen for treating metastatic nasopharyngeal carcinoma (NPC) but it is limited by severe stomatitis and chronic cisplatin-related toxicity. A novel approach including induction with mitomycin C, doxorubicin and cisplatin (MAP) and subsequent maintenance with weekly 5-FU and leucovorin (FL) were designed with an aim to reduce acute and chronic toxicity of PF. Thirty-two patients of NPC with measurable metastatic lesions in the liver or lung were entered into this phase II trial. Mitomycin C 8 mg m(-2), doxorubicin 40 mg m(-2) and cisplatin 60 mg m(-2) were given on day 1 every 3 weeks as initial induction. After either four courses or remission was achieved, patients received weekly dose of 5-FU 450 mg m(-2) and leucovorin 30 mg m(-2) for maintenance until disease progression. With 105 courses of MAP given, 5% were accompanied by grade 3 and 0% were accompanied by grade 4 stomatitis. The dose-limiting toxicity of MAP was myelosuppression. Forty per cent of courses had grade 3 and 13% of courses had grade 4 leukopenia. No grade 3 or 4 cisplatin-related toxicity was observed. The overall response rate was 94% (95% confidence interval (CI) 84.9-100%) with a complete response rate (CR) of 6% (95% CI: 0-15.2%) and a good partial response (PR) rate of 28% (95% CI 11.7-44.6%), which was optionally defined as observance of only equivocal lesion identifiable under imaging study. Twenty-seven cases entered weekly FL maintenance phase. The median duration of maintenance with weekly FL was 38 weeks (8-91 weeks). There was no grade 3 or 4 toxicity noted during weekly FL. The median progression-free survival and overall survival were 11.6+/-0.4 and 18.1+/-3.6 months respectively. Six patients with a median follow-up of 19.8 months (9.6-41.0 months) were still alive and five of them had disease under control with FL. Good responders (CR and good PR) had better survival than less satisfactory responders (PR and stable disease) (P = 0.05). From Cox's multivariate regression analysis, the only significant prognostic factor for survival was good response to MAP (P = 0.042). Liver metastasis was the only significant variable in the best subset regression model that predicted good response to MAP (CR and good PR) (P = 0.027). MAP was an effective combination for metastatic NPC with minimal stomatitis and cisplatin-related toxicity but had significant myelosuppression. Weekly FL was a maintenance therapy with minimal side-effects. The response rate and overall survival of MAP-FL were better than series previously reported even when a subset of patients with poor prognosis was selected. MAP-FL's role as neoadjuvant or adjuvant therapy is worthy of further study.

Adult↗
PubMed2005

Deep sclerectomy augmented with mitomycin C.

AIMS: To investigate the comparative efficacy and safety of deep sclerectomy with and without intraoperative mitomycin C (MMC) application for lowering the intraocular pressure (IOP). METHODS: A total of 71 eyes of 71 consecutive patients who had routine deep sclerectomy (DS), nonaugmented (DS-noMMC) or with mitomycin C (DS-MMC) augmentation (0.2 mg/ml for 2 min) and follow-up of 4 months or more were identified from an ongoing prospective database on glaucoma surgery. Indications for MMC use were the presence of risk factors for subconjunctival scarring and low target IOPs. MMC 0.2 mg/ml was applied in the sub-Tenons space for 2 min. RESULTS: There were 19 eyes in the DS-noMMC group and 52 eyes in the DS-MMC group. In 11 eyes (15.5%), the procedure was complicated by intraoperative perforation of the trabeculo-Descemet's window. Eyes in the DS-MMC group had significantly lower IOPs (MANOVA, P = 0.04). Kaplan-Meier survival curve analysis showed that the probability of maintaining IOP below target IOP level, below 18 mmHg and below 14 mmHg at 1 year was 51, 67, and 35% for the DS-noMMC group and 80, 86, and 74% for the DS-MMC group. The survival rates of the DS-MMC group were not statistically significant (P = 0.06) when the success criterion was maintaining an IOP less than 18 mmHg but were significant for the other criteria, namely IOP less than target levels (P = 0.03) and less than 14 mmHg (P = 0.03). Nd:YAG goniopuncture to lower IOP to target levels was done more frequently in the DS-noMMC group (13 eyes, 81%) than the DS-MMC group (20 eyes, 45%) and this difference was significant (P = 0.03). The prevalence of avascular areas within filtration blebs and transconjunctival oozing of aqueous was significantly higher in the DS-MMC group (P < 0.01). CONCLUSIONS: The use of intraoperative MMC during deep sclerectomy has a significant effect on the postoperative IOP and increases the probability of achieving target IOPs. However, our current technique of MMC application is associated with a higher incidence of avascular blebs and transconjunctival oozing.

Aged↗
PubMed2005

Fornix vs limbal-based trabeculectomy with mitomycin C.

PURPOSE: To compare the effectiveness of limbus- and fornix-based conjunctival flaps in patients undergoing trabeculectomy with mitomycin-C augmentation. METHODS: A retrospective review of the records of 71 consecutive eyes of 59 patients who underwent trabeculectomy with mitomycin C. All the patients had at least 6 months of follow-up. The first 35 eyes underwent surgery with a limbal-based flap, whereas all subsequent surgeries were by fornix-based procedures. RESULTS: No significant difference was detected between the groups with regard to patient demographics, preoperative visual field and intraocular pressure parameters, postoperative intraocular pressures at day 1, months 1, 3, and 6 postoperatively, need for intervention, need for supplementary glaucoma medication, and final visual acuity. There were four cases of overdrainage and hypotony in the limbal-based group, whereas none occurred in the fornix-based group. In all 83% percent of eyes in the limbal-based group achieved intraocular pressures off medication of less than 18 mmHg, whereas 94% of the fornix based group obtained such IOP control. One patient in the limbal-based group developed late postoperative endophthalmitis. CONCLUSION: Trabeculectomy with MMC augmentation is a safe and effective procedure for reduction of IOP and visual rehabilitation whether a fornix- or a limbal-based conjunctival flap is utilised. In this series, there was a greater risk of excessive drainage with subsequent hypotonous complications when surgery was undertaken by a limbal-based procedure.

Adult↗