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PubMed2004

A pilot study of neoadjuvant chemotherapy with mitomycin C, etoposide, cisplatin, and epirubicin for adenocarcinoma of the cervix.

BACKGROUND: To evaluate the efficacy and toxicity of the combination of mitomycin C, etoposide, cisplatin, and epirubicin (MEPA) as neoadjuvant therapy for patients with cervical adenocarcinoma. METHODS: Fourteen patients with cervical adenocarcinoma received neoadjuvant MEPA therapy followed by radical hysterectomy. The International Federation of Gynecology and Obstetrics stage was: IB1 in 2 patients, IB2 in 5, and IIB in 7. The MEPA regimen consisted of mitomycin C (15 mg/m2) on day 1, etoposide (70 mg/m2) on days 1 to 3, cisplatin (15 mg/m2) on days 1 to 5, and epirubicin (30 mg/m2) on day 1, with this course being repeated every 4 weeks. After two or three courses of chemotherapy, all patients underwent radical hysterectomy. Postoperative radiotherapy was given to 6 patients who showed risk factors at surgery. RESULTS: Of the 14 patients, 7 had complete remission (CR) clinically, 6 had partial remission, and only 1 showed no change. Examination of surgical material revealed no residual disease in 6 patients, and microscopic residual disease (<5 mm) in 2 patients. The patients who had no residual disease or microscopic disease in their hysterectomy specimens showed a significantly longer survival than those with macroscopic residual disease (P = 0.012). The dose-limiting toxicity was myelosuppression. Of the 33 treatment cycles administered, leukopenia of grade 3 or more occurred in 70%,and thrombocytopenia of grade 3 or more occurred in 79%. There were no therapy-related deaths. CONCLUSION: Although severe myelosuppression was also observed, there was a satisfactory response rate to MEPA therapy, which showed a good pathological CR rate.

Adenocarcinoma↗
PubMed1993

Mitomycin C stimulates the expression of human immunodeficiency virus long terminal repeat sequences in rat and human fibroblasts.

We have employed a recombinant plasmid, pBHIV1, carrying the long terminal repeat (LTR) sequences of the human immunodeficiency virus-1 (HIV-1) linked to the reporter chloramphenicol acetyl transferase (CAT) gene and to the aminoglycoside phosphotransferase (aph) gene as a selectable marker. We have introduced pBHIV1 into rat 208F and human MRCSV40TGR fibroblasts and obtained stable geneticin resistant RFBHIV1-1 and SVTGHIV1-1 cells, respectively. Both transfectant cells express CAT activity from the HIV LTR promoter. The response to the antineoplastic drug mitomycin C was studied on the LTR regulated CAT activity in both cell lines. It was found that mitomycin C at 10 micrograms/mL concentration stimulates the expression of CAT from the HIV LTR 77-fold in rat RFBHIV1-1 and 3.1-fold in human SVTGHIV1-1 cells.

Animals↗
PubMed1993

Ultraviolet light, mitomycin C and nitrous acid induce genetic instability in Streptomyces ambofaciens ATCC23877.

In Streptomyces ambofaciens ATCC23877, pigment-negative (Pig-) mutants occur at high frequency (about 0.7 x 10(-2)) in the progenies of wild-type colonies. Furthermore, the offspring of these Pig- mutants can either be phenotypically homogeneous or hypervariable (with no preponderant phenotype). Pig- mutants can also lack antibiotic production and present aerial mycelium deficiency, auxotrophy for arginine, oversensitivity to either ultraviolet (UV) light or mitomycin C and resistance to either novobiocin or nosiheptide. This genetic instability is related to both amplified DNA sequences and deletions. Mutagens such as UV light, mitomycin C and nitrous acid induced genetic instability and increased the Pig- mutant frequency to almost 30% even at a high survival rate. Induced Pig- mutants exhibited the same features as the spontaneous ones at both phenotypic and molecular levels. The frequency of detected genomic rearrangements after treatment was higher than 10%. We postulate that an SOS-like system is involved in the induction of genetic instability in S. ambofaciens.

Gene Rearrangement↗
PubMed1994

Micronuclei and mitotic index in B-, T4- and T8-cells treated with mitomycin C and gamma-irradiation.

Lymphocytes were treated in vitro with mitomycin C and gamma-radiation at different doses (0-250 nmol/l and 0-2 Gy, respectively). After incubation in RPMI 1640 medium and stimulation with phytohemagglutinin for 72 h, the lymphocyte subgroups T4 (CD4), T8 (CD8) and B (CD19) were separated by an immunomagnetic method and analyzed for the presence of micronuclei. With mitomycin C the highest levels were found in T4- and B-cells. When micronuclei were induced by irradiation the T4-cells showed the highest frequencies and the B-cells the lowest. The outcome of B-cells with gamma-irradiation was probably due to a pronounced cytotoxic reaction in this cell type, which could be measured as a decrease in mitotic index.

B-Lymphocytes↗
PubMed1991

Mitomycin-C/5-FU and radiation therapy for locally advanced uterine cervical cancer.

To assess the feasibility and effectiveness of combined therapy on locally advanced cervical cancer, we entered 38 patients into a study. The patients were treated with mitomycin-C (10 mg/m2) on Days 1 and 30 and 5-FU (1000 mg/m2) on Days 1 to 4 and Days 30 to 33. In 5 weeks 4500-5000 cGy was given concurrently, followed by radioactive implants. Twenty-six patients had an early-stage disease (IB-IIB) and twelve had a late-stage disease (IIIB-IVA). Eighty-seven percent (33/38) of the patients had a tumor measuring 5 cm or more. The other 5 patients with a tumor size under 5 cm had biopsy-proven positive pelvic nodes; 2 of these 5 patients had a pretherapy hysterectomy. Tumor response, complete (CR) vs partial (PR), was assessed in 36 patients 3 months after completion of therapy. A CR was noted in 80% (29/36) of the patients. The PR status conferred a detrimental effect on the pelvic disease control (PDC), disease-free survival (DFS), and survival (S) while late stage correlated with the development of distant metastases (DM) and a poor DFS. PDC was obtained in 93% (27/29) of the patients who had a CR, as compared to only 43% (3/7) of those with a PR (P = 0.0228). The DFS and S rates were 59 and 77% for patients with a CR and 21 and 19% for those with a PR; respective P values were 0.0340 and 0.0002. Eleven percent (3/26) of the patients with an early stage developed DM, as compared to 50% (6/12) of those with late stage, (P = 0.0016). The DFS rates were 80 and 37% for patients with an early and late stage, respectively (P = 0.0141). Four patients developed transient neutropenia and one had transient thrombocytopenia. The second dose of mitomycin-C was omitted in 4 patients due to persistent neutropenia in 3 and to transfusion-related hepatitis in 1. Two percent (5/21) of the patients who had a staging laparotomy developed wound dehiscence. Three patients developed non-cancer-related small bowel obstruction requiring surgery. We concluded that this combined regimen was well tolerated. Although it was effective in controlling the cancer in the pelvis, this regimen failed to control DM in late-stage patients.

Adult↗
PubMed1995

Assessment of micronucleus induction in SCCVII cells treated with bioreductive agents, WIN 59075 (SR 4233) and mitomycin C, under aerobic and hypoxic conditions.

WIN 59075 (SR4233, tirapazamine) is a promising bioreductive antitumor agent preferentially more toxic to hypoxic cells and presently undergoing phase I clinical trials. In this investigation, we have examined the applicability of the cytokinesis-block micronucleus assay to assess the effects of bioreductive agents. SCCVII tumor cells were treated with WIN 59075 or mitomycin C at various concentrations under aerobic and hypoxic conditions. Significant induction of micronuclei in binucleate cells was demonstrated in a dose-dependent fashion and it appeared to be strongly correlated with the loss of clonogenicity in the colony assay. Both agents showed selectively higher toxicity to hypoxic cells than to aerobic cells and the ratios of the concentrations required to obtain the equivalent effects under aerobic and hypoxic conditions could be also estimated by this method as follows: the hypoxic toxicity ratios were 120-130 for WIN 59075 and 3.0-3.3 for mitomycin C. For several favorable characteristics, the cytokinesis-block micronucleus assay can provide an alternative, rapid, and reproducible means for evaluation of antitumor activities from chromosomal breakage caused by the bioreductive agents.

Dose-Response Relationship, Drug↗
PubMed1988

SOS independent survival against mitomycin C induced lethality in a rifampicin-nalidixic acid-resistant mutant of Escherichia coli.

A combination of specific rifampicin-resistant (rpoB87) and nalidixic acid-resistant (gyrA87) mutations results in a marked increase in the survival of Escherichia coli against mitomycin C-induced lethality in mutants defective for SOS induction and excision repair. Although the response does not seem to be obligatorily dependent upon the RecA protein, the efficiency is markedly increased in its presence, even in a conventionally inactive form. This response is not elicited against lethality due to ultraviolet radiation or N-methyl-N' -nitro-N-nitrosoguanidine exposure. The combination of rpoB87 and gyrA87 mutations also greatly alleviates post-mitomycin C degradation of DNA under SOS non-inducible conditions. It is proposed that the rpoB subunit of RNA polymerase and gyrA subunit of DNA gyrase could participate in the repair of certain types of DNA damage, such as cross-links, in a mode independent of SOS-regulated excision repair and post-replication repair.

DNA Repair↗
PubMed1996

Efficacy and toxicity of mitomycin, ifosfamide, and cisplatin (MIP) in patients with inoperable non-small cell lung cancer.

Seventy-two patients with advanced stage IIIB (42%) or stage IV (58%) non-small cell lung cancer (median age 57 years, Karnofsky PS 60-100) were treated with mitomycin C (6 mg/m2, day 1), ifosfamide (1500 mg/m2, days 1-3), and cisplatin (30 mg/m2, days 1-3) every 4 weeks. The objective response rate was 37% in the overall population; 50% in stage IIIB patients and 29% in stage IV patients. Twenty four patients achieved partial response (33%) and three patients achieved complete response. Despite this relatively high objective response rate, the overall median survival time was 32 weeks. The median survival was significantly better in stage IIIB patients (55 weeks) than in stage IV patients (25 weeks) (P = 0.003). MIP regimen was permanently suspended in 14 patients because of toxic events. Seventeen patients developed grade III or IV febrile neutropenia and two patients died from sepsis. Two patients experienced acute mitomycin peumonitis. Despite increased doses of cisplatin and ifosfamide, compared with the original description for MIC chemotherapy, with probably higher toxicity, no apparent increased response rate or median survival was observed in this study. The MIP regimen could be tested in a randomized trial in comparison with other administration plans in a comparable population.

Adult↗
PubMed1989

Cardiac, renal, and pulmonary toxicity of several mitomycin derivatives in rats.

The potential cardiotoxicity, nephrotoxicity, and pulmonary toxicity of several mitomycin (MMC) derivatives, BMY-25067 (N-7-[2-(4-nitrophenyldithio)ethyl]MMC), BMY-26107 (N-7-[2-(4-aminophenyldithio)ethyl]MMC), BMY-26605 (N-7 acetyl-MMC), BMY-25690 (7-N-(dimethylaminomethylene)-10-[1-morpholinomethyleneamino)carbo nyl- oxy]MMC), BMY-26646 (N-7-[2-(4-fluorophenyldithio)ethyl]MCC), and BMY-25551 (7-(2-hydroxyethyl)mitosane), were evaluated in rats. Groups of 10 male Sprague-Dawley rats were given single intravenous doses of the test compounds and were then observed for 10 weeks. Doses represented 67 and 33% of the respective mouse LD10 (corrected for body size on a mg/m2 basis) of each test compound. BMY-25282 (7-N-(dimethylaminomethylene)MMC), a mitomycin derivative that produces cardiac, renal, and arterial lesions, was used as a reference drug. Hematologic and blood chemical parameters were monitored at 3 days and at 3, 6, and 10 weeks after drug administration. Heart, kidney, and lung were examined histopathologically. Drug-related cardiac changes with late onset were seen histopathologically in rats treated with BMY-26605, BMY-25282, BMY-25551, and BMY-25690 (in order of decreasing severity). Drug-related renal changes, consisting of tubular degeneration and glomerulopathy, were seen in rats treated with BMY-25690, BMY-26107, BMY-25282, BMY-25551, BMY-26605, and BMY-25067 (in order of decreasing severity). Pulmonary arterial lesions were noted inconsistently in rats treated with BMY-26605, BMY-25282, and BMY-25551. Neither cardiac, renal, nor pulmonary changes were seen in rats administered BMY-26646, and only minor drug-related renal changes were seen in rats treated with BMY-25067.

Animals↗
PubMed1986

Vindesine and mitomycin C in inoperable non-small cell lung cancer.

Twenty-nine patients with inoperable non-small cell lung cancer were treated as out-patients with vindesine and mitomycin C. Eight patients had a complete response, and nine a partial response. Response was generally associated with either stable or improving ECOG and symptom scores. The incidence of serious side-effects was low--only two patients' white cell count fell below 3000 cells/mm2, only one patient's platelet count fell below 100,000 cells/mm2, and two patients developed vomiting associated with treatment. The combination of vindesine and mitomycin C appears to be effective in the treatment of inoperable non-small cell lung cancer. Side effects were generally well tolerated and allowed out-patient treatment.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

Ifosfamide and mitomycin in combination for the treatment of patients with progressive advanced non-small cell lung cancer.

42 patients with progressive and advanced non-small cell lung cancer received chemotherapy comprising ifosfamide 1.5 g/m2, mesna 1.5 g/m2 and mitomycin 1.2 mg/m2 daily for 5 days. Only those patients with symptoms and progressive disease were selected for treatment. Partial response was achieved in 10/42 patients (23.8%) and stable disease in 25/42 (59.5%). The Karnofsky performance status (KP) improved in 10/42 patients (23.8%) and a subjective respiratory symptom score improved in 12 patients (28.6%). In addition 27 patients (64.3%) had stabilisation of both the KP and respiratory score following chemotherapy. These results indicate that the ifosfamide and mitomycin combination is active in non-small cell lung cancer in this selected group of patients with antitumour and symptom control activity.

Adenocarcinoma↗
PubMed1991

Pharmacokinetics of bronchial artery infusion of mitomycin in patients with non-small cell lung cancer.

The pharmacokinetics of bronchial artery infusion of 20 mg (11.4-14.0 mg/m2) mitomycin was studied in 14 patients with non-small cell lung cancer (NSCLC). The mean elimination half-life was 34.3 min (range 6-72), and the area under the plasma concentration-time curve (AUC) was 166 ng h/ml (39-312). The mean maximum plasma drug concentration (Cmax) was 178 ng/ml (12-540) and back-extrapolated plasma drug concentration was 308 ng/ml (17-1423). The mean volume of distribution in the one-compartment model was 0.183 l/kg (0.010-0.887) and the rate constant for unchanged drug appearing in the urine was 1.91/min (0.57-7.27). There was considerable variation among individuals with respect to the pharmacokinetics of mitomycin, and the mean Cmax and AUC were lower than those reported after intravenous administration.

Bronchial Arteries↗
PubMed1992

Phase I study of BW12C in combination with mitomycin C in patients with advanced gastrointestinal cancer.

The effect of combining the oxyhemoglobin-modifying drug BW12C with mitomycin C was investigated in a Phase I study of 18 patients with advanced gastrointestinal cancer. The dose of BW12C was increased from 20 mg/kg to 50 mg/kg to modify the hemoglobin-oxygen saturation curve by up to 48%. The period of maximum modification was then prolonged for up to 3 hr by a maintenance infusion of 4-6 mg/kg/hr. Pharmacokinetics of BW12C and mitomycin C were performed in all patients. Peak levels of BW12C increased from 139 micrograms/ml to 378 micrograms/ml. Plasma half life was independent of dose, with an average of 3.3 hr. BW12C was well tolerated with no severe side effects. Three patients had objective tumour responses.

Adenocarcinoma↗
PubMed1993

A randomized trial of radiation therapy compared to split course radiation therapy combined with mitomycin C and 5 fluorouracil as initial treatment for advanced laryngeal and hypopharyngeal squamous carcinoma.

Two hundred and twelve patients with previously untreated advanced squamous carcinoma of the larynx or hypopharynx were randomized to receive initial treatment with radiotherapy, 50 Gy in 20 fractions in 28 days or split course radiotherapy and concurrent chemotherapy, 25 Gy in 10 fractions in 14 days followed by a 4 week rest and a further 25 Gy in 10 fractions in 14 days starting on day 43; Mitomycin C was given on day 1 and day 43 and 5FU continuous infusions on days 1--4 and days 43--46. Surgery was reserved for persistent or recurrent disease. Two hundred and nine of the 212 patients randomized were included in the analyses. Outcome analyses were performed at a median follow-up interval of 4.4 years. No patients were lost to follow-up. No significant difference was found between the two arms for the end points of local relapse-free rate (p = 0.91), regional relapse-free rate (p = 0.17, adjusted) or overall survival (p = 0.86). Eight-eight patients had attempted surgical resection following radiotherapy failure. The contribution of salvage surgery to overall survival was similar for both arms of the study as was the surgical complication rate. Serious late radiation toxicity was minimal (3% in the RT group, 0% in the radiation therapy plus chemotherapy group). The result of the trial shows no advantage in terms of local control or survival for the experimental treatment arm of split course radiotherapy and concurrent chemotherapy with Mitomycin C and 5 Fluorouracil compared to radiotherapy alone.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1994

Combination therapy with radiation, mitomycin C, and 5-fluorouracil in EMT6 tumors.

PURPOSE: The primary purpose of these studies was to assess whether concomitant treatment with 5-fluorouracil increased the cytotoxicity of radiation, mitomycin C, or the combination of these two agents to cells in solid tumors. METHODS AND MATERIALS: All studies were performed using EMT6 mouse mammary tumor cells. In vitro studies used exponentially-growing monolayers. In vivo studies used solid EMT6 tumors growing in BALB/c Rw mice. The effects of treatment on tumors or cultures were assessed using clonogenic assays which considered both the colony forming abilities of the intact cells and the numbers of cells in the cultures or tumors. RESULTS: EMT6 cells in vitro were killed effectively by 5-fluorouracil. The cytotoxicity increased as the drug concentration increased from 1 microM to 1 mM or as the treatment time increased from 1 to 48 hr. However, 5-fluorouracil was only marginally active against solid EMT6 tumors: treatment with doses of up to 400 micrograms/gm killed less than 50% of the tumor cells, regardless of whether the drug was given as an injection or an infusion over 48 hr and regardless of the time between injection of the drug and assay of cell survival. Treatment with 5-fluorouracil produced only a statistically insignificant increase in the effect of 15 Gy of x-rays, whether the drug was given by injection or infusion over 48 hr. Both injection of 200 micrograms/g 5 FU and infusion of 100 micrograms/g 5-fluorouracil decreased the cytotoxicity of 6 micrograms/g of MC to cells in solid tumors. Injection of 200 micrograms/g of 5-fluorouracil decreased the cytotoxic effects of a regimen combining 6 micrograms/g MC plus 15 Gy of x-rays. CONCLUSION: In this solid tumor system, a regimen combining single doses of mitomycin C and x-rays was more effective in killing the tumor cells than was the same regimen combined with 5-fluorouracil.

Animals↗
PubMed1992

Mitozantrone and methotrexate chemotherapy with and without mitomycin C in the treatment of advanced breast cancer: a randomised clinical trial.

Patients with advanced breast cancer were randomised to 3M (mitozantrone 6.5 mg/m2q 21 days, methotrexate 30 mg/m2q 21 days, mitomycin C 6.5 mg/m2q 42 days) or 2M (as 3M but without mitomycin C). The objective response rates of 30% in 51 evaluable patients receiving 3M and 26% of 54 patients receiving 2M were not significantly different. 4/16 patients not responding to 2M responded to 3M on crossover. Both regimes were well tolerated but there was significantly less haematological toxicity and fewer dose reductions and delays with 2M. We conclude that patients should initially be treated with 2M and that non-responding patients should be crossed to 3M.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

Unexpected prolonged myelosuppression after mitomycin, mitoxantrone and methotrexate.

28 patients (26 with breast cancer and 2 with colon cancer) received mitomycin, mitoxantrone and methotrexate (MMM). Half the patients had grade III-IV leukopenia and 29% had grade III-IV thrombocytopenia. The median time of recovery to WHO grade 0 was 62 and 128 days, respectively. Thrombocytopenia and leukopenia were more frequent and longer lasting after the three-drug part of the therapy, which suggests a critical role for mitomycin in this toxicity.

Adult↗
PubMed1994

Combination chemotherapy with epirubicin and mitomycin C as first-line treatment in advanced breast cancer.

From December 1988 to February 1991, 112 consecutive patients were submitted to epirubicin + mitomycin C chemotherapy as first-line treatment for advanced breast cancer. Epirubicin (75 mg/m2) was given every 3 weeks and mitomycin C (10 mg/m2) every 6 weeks. Only patients with visceral involvement or with a disease-free interval of less than 12 months were considered eligible. 102 patients were evaluated for response and toxicity in the present analysis. The main sites of involvement were viscera, soft tissues, bone in 71 (69.6%), 19 (18.6%) and 12 (11.8%) patients, respectively. Multiple site involvement was present in 66 (64.7%) cases. A total of 726 courses of therapy were administered (range 2-14; mean 7.2). Follow-up ranged from 96 to 210 weeks (median follow-up 138 weeks). Response rate was complete response (CR): 21.6% [95% confidence interval (CI) +/- 0.8], partial response (PR) 49.0% (95% CI +/- 0.1), stable disease (SD) 12.7% (95% CI +/- 0.1), progressive disease (PD) 16.7% (95% CI +/- 0.1), CR + PR: 70.6% (95% CI +/- 0.1). Median values of survival and time to progression were 79.4 and 42 weeks, respectively. At 2 years, 37.2 +/- 4.7% and 12.8 +/- 3.3% of the patients, respectively, were alive or without evidence of progression. Toxicity was generally mild. One hundred and four (14.3%) cycles in 53 patients were delayed due to haematological (82) or cardiac (3) toxicity, infectious disease (11) or causes not related to the treatment (8).

Adult↗