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PubMed2006

Increased sensitivity to mitomycin C-induced sister chromatid exchange in lymphocytes from patients undergoing hyperbaric oxygen therapy.

Treatment of cells with hyperbaric oxygen (HBO) results in the generation of reactive oxygen species and the induction of DNA damage. In the present study, we have evaluated the sister chromatid exchange (SCE) frequencies in lymphocytes from patients undergoing hyperbaric oxygen therapy (HBOT). In addition, we have determined the sensitivity of lymphocytes from those patients to SCE induction by 20 and 40 ng/ml mitomycin C (MMC). Patients undergoing HBOT for diabetic feet were exposed to 10 consecutive daily HBO treatments according to a routine therapy protocol. The study began with 12 patients; however, it was not possible to sample all of the patients at all HBOT sessions, and the number of patients gradually decreased towards the end of the HBOT. We observed a statistically significant induction in mean SCE/cell (P < 0.05; n = 11) immediately after the first session of HBOT. Relative to its frequency after the 1st treatment, the mean SCE frequency gradually decreased after the 5th and 10th HBOT sessions and reached baseline (pretherapy) levels 1 day after the last treatment in the four patients that were sampled. The mean MMC-induced SCE frequency was highest in lymphocytes sampled immediately after the first HBOT session, and significantly higher than the MMC-induced SCE frequency in cells sampled before HBOT. Unlike the case with untreated cells, MMC-induced SCE frequencies remained high in lymphocytes sampled at later stages of therapy and mean MMC-induced SCE frequencies were significantly higher (P < 0.05; n = 4) in lymphocytes sampled 1 day after the last session of HBOT than in lymphocytes sampled from these patients prior to beginning the therapy. The results indicate that HBOT induces SCE and that lymphocytes retain increased sensitivity to the genotoxicity of MMC one day after completing the HBOT.

Adult↗
PubMed1989

Absence of mutagenic interaction between microwaves and mitomycin C in mammalian cells.

Evidence in the literature from in vitro and in vivo studies as to whether or not radiofrequency radiation (RFR) in the microwave range is mutagenic is predominantly negative, with some positive reports. No evidence is available as to whether RFR will alter the mutagenic activity of genotoxic chemicals during a simultaneous exposure, a likely real-life situation. Two hypotheses have been proposed: a) that RFR by itself can cause mutations in a mammalian cell in vitro assay system; and b) that a simultaneous exposure to RFR during a chemical treatment of the cells with a known genotoxic agent, mitomycin C (MMC), will alter the extent of mutagenesis induced by the treatment of the cells by the chemical alone. These studies were performed using the forward mutation assay at the thymidine kinase locus in L5178Y mouse leukemic cells. The pulsed wave RFR was broadcast from an antenna horn at a frequency of 2.45 GHz. The power density was 48.8 mW/cm2 and the measured specific absorption rate (SAR) in this system was 30 W/kg (600 W forward power), which is well above current safety guidelines. The conclusions from five different experiments, employing three different concentrations of MMC, were that a) RFR exposure alone, at moderate power levels which resulted in a temperature increase in the cell culture medium of less than 3 degrees C, is not mutagenic; and b) when cells are simultaneously treated with MMC and RFR at these same moderate power levels, the RFR does not affect either the inhibition of cell growth or the extent of mutagenesis resulting from the treatment with the chemical MMC alone.

Animals↗
PubMed1984

Comparison of methods for detecting mitomycin C- and ethyl nitrosourea-induced germ cell damage in mice: sperm enzyme activities, sperm motility, and testis weight.

Testes weights, sperm motility and enzyme activities in single sperm were compared with respect to their ability to detect either developmental or mutational damage to germ cells. Male mice were injected i.p. with 2.5 mg/kg mitomycin C (MC) or 50 or 100 mg/kg ethylnitrosourea (ENU) or saline and were then killed at times such that sperm derived from treated vas sperm (SZ), spermatids (ST), preleptotene-late-spermatogonial cells (PLSG), spermatogonial cells (SG), or spermatogonial stem cells (SGS) could be evaluated. Testis weights decreased significantly as early as 1 wk after treatment, with the greatest decrease reached 3-4 wk after treatment, followed by recovery to normal levels 10-15 wk after treatment. We conclude that testis weight, which is easily obtained, is a sensitive indicator of germ cell damage by these agents. Sperm from each animal were evaluated for sperm motility, acrosin activity, succinic dehydrogenase (SDH) activity with or without the competitive inhibitor malonate or after exposure to 60 degrees C for 10 min. The latter two assays were to detect sperm enzymes resistant to the inhibitor or heat. The presence of the acrosin protein was also detected immunologically. Sperm motility decreased most from treatment of PLSG and SG. After MC or ENU treatment, the greatest loss of acrosin activity and of the acrosin protein was also noted in sperm derived from treated PLSG and SG. MC and ENU failed to induce SDH activity in single sperm resistant to 60 degrees C heat inhibition or to inhibition by malonate. Of the sperm assays, acrosin activity proved to be the most sensitive indicator of germ cell damage and was the simplest to measure.

Acrosin↗
PubMed1985

Chromosome fragments and other abnormalities induced by mitomycin C in the neuroblast of Chortophaga viridifasciata.

Mitomycin C (MMC) induces acentric chromosome fragments in the neuroblast (Nb) of the grasshopper embryo (Chortophaga viridifasciata) after acute and chronic exposure to concentrations ranging from 10(-8) to 10(-4) M, the dose response being essentially linear up to 10(-5) M. Because Colcemid is not used in the Nb assay, it was possible to detect two additional effects of MMC: (1) Prolonged retardation of many cells occurs when they reach very late prophase; the chromosomes continue condensing and lose their orderly prophase orientation, and the nuclear envelope becomes increasingly fragile. Such cells, which were observed after both acute and chronic exposure, give the false impression of being c-metaphases when they are fixed and squashed. The frequency of retarded very late prophases and the duration of retardation are related to MMC concentration and time of exposure. A rationale is presented supporting the idea that the events associated with retarded very late prophase result from MMC effects on the nuclear envelope. (2) MMC significantly increases the frequency of Nb's with attenuated centromeres at the beginning of early anaphase, an effect that appears to be caused by a delay in the repulsion of sister chromatids that usually occurs immediately after centromere separation begins.

Anaphase↗
PubMed1987

Effects of radiofrequency radiation and simultaneous exposure with mitomycin C on the frequency of sister chromatid exchanges in Chinese hamster ovary cells.

Chinese hamster ovary (CHO) cells were exposed for 2 hr with and without mitomycin C (MMC) (1 X 10(-8)M) to pulsed wave radiofrequency radiation (RFR) at 2450 MHz. The repetition rate of 25,000 pulses per sec (pps), pulse width of 10 microseconds, and exposure geometry used, resulted in a specific absorption rate (SAR) of 33.8 W/kg. The following exposure regimens were used: a 37 degrees C water bath control; a water bath temperature control (TC) in which the continuously monitored medium temperature closely followed the temperature rise in the RFR-exposed flasks; and the RFR-exposed cells in a water bath set at 37 degrees C prior to exposure. RFR exposure resulted in a maximum cell culture medium temperature of 39.2 degrees C. In the absence of MMC, there was no significant increase in sister chromatid exchange (SCE) in the RFR-exposed or TC groups over that of the 37 degrees C control. When a simultaneous treatment of RFR and MMC occurred there was no statistical difference in SCE frequency from that caused by chemical treatment alone.

Animals↗
PubMedDate not supplied

A phase II clinical trial of the combination mitomycin C, adriamycin, and cis-diamminedichloroplatinum in patients with advanced upper aerodigestive cancer.

Twenty-seven patients with assessable, regionally advanced, or metastatic upper aerodigestive cancer of diverse histology received a combination of mitomycin C, adriamycin, and cis-diamminedichloroplatinum. All patients had previously received extensive surgery and/or radiation therapy. We observed an overall 46% partial response rate (12/26). This included seven of 15 (47%) responders with squamous cell carcinoma. Six of those seven patients responded within the initial month of treatment. For all study participants, the median time to progression and survival was 3.8 months and 7.3 months, respectively. Moderate-to-severe nausea, vomiting, anorexia, and alopecia were the most common toxicities. Myelosuppression (WBC less than 4,100 cells/mm3) and thrombocytopenia (PLTS less than 130,000 cells/mm3) occurred in 100% and 71% of the 21 patients with nadir data recorded, respectively. There were no episodes of sepsis nor did we detect any meaningful impairment in renal function. This regimen is active in the previously treated head and neck cancer patient and can be conveniently administered on an outpatient basis with acceptable and manageable side effects.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1984

Modulation of anti-tumour immunity induced by syngeneic mitomycin C-treated murine tumour cells.

Experiments were performed to examine the kinetics of delayed-type hypersensitivity (DTH) to mitomycin-C-treated syngeneic murine fibrosarcomas inoculated into the footpads of mice. Evidence is presented to show that a "strongly" antigenic tumour, designated H7, elicits consecutive waves of footpad swelling in both primary and secondary responses. Periods of anti-tumour resistance coincided with the expression of each successive wave of footpad swelling in normal and immune mice. The down-regulation of the response, between the successive peaks of footpad swelling, was accompanied by active tumour growth. In contrast, the non-cross-reacting "weakly" antigenic tumour, designated H1, induced footpad swelling which was expressed only once after either primary or secondary sensitization. Unlike that induced by the "strongly" antigenic H7 tumour, the anti-tumour immunity to the H1 tumour was not sustained beyond its initial specific phase. Consequently, H1 tumour cells which survived the initial phase of anti-tumour immunity appeared to encounter no further resistance. Thus the distinctive feature of the "weakly" antigenic H1 tumour was its inability to sustain consecutive waves of tumour resistance as exhibited by the "strongly" antigenic H7 tumour. It is proposed that "weakly" and "strongly" antigenic tumours are distinguished by their different abilities to down-regulate the anti-tumour immune response. The "weakly" antigenic tumour induces specific immunity which is rapidly down-regulated while that induced by the "strongly" antigenic tumour is sustained by successive waves of anti-tumour activity of diminishing intensity. Suppression of some but not all waves of footpad swelling occurred in mice with growing H7 tumours.

Animals↗
PubMed1985

Antitumor effects of two polyamine antimetabolites combined with mitomycin C on human stomach cancer cells xenotransplanted into nude mice.

The antitumor effects of alpha-difluoromethylornithine (DFMO), methylglyoxal-bis-guanylhydrazone (MGBG) and mitomycin C (MMC), administered separately or in various combinations, on human stomach cancer cells xenotransplanted into BALB/c nude mice were studied using the protocol of Battelle's Columbus Laboratories (Ovejera et al., 1978). DFMO (1,000 mg/kg in 2 divided doses) and MGBG (50 mg/kg) were given intraperitoneally (i.p.) for 7 consecutive days from the time when the tumor weighed about 100 mg. MMC (2 mg/kg) was given i.p. every other day from the same time. Animals treated with either DFMO or MGBG alone displayed tumor growth comparable to that seen in untreated controls. In mice treated with DFMO plus MGBG with or without MMC, or in mice treated only with MMC, tumor growth was significantly lower than in untreated mice. In the group which received only combined DFMO/MGBG there was a rapid regrowth of the tumor after termination of therapy. Tumor putrescine levels decreased within 4 days following the administration of DFMO; however, spermidine levels did not decline with either DFMO or MGBG treatment even after 7 days. When combined DFMO/MGBG was given, there was a significant decline in spermidine levels 7 days after the initiation of treatment. In contrast, when MMC alone was administered, putrescine and spermidine levels in the tumor did not differ from those in control mice. Spermine decreased markedly in tumor with the combined administration of DFMO/MGBG as well as with combined DFMO/MGBG/MMC, but decreased only slightly when MMC alone or MMC plus either DFMO or MGBG was administered. By the 7th treatment day, DNA biosynthesis in the tumor had dropped markedly in all groups except those receiving DFMO or MGBG alone.

Adenocarcinoma, Papillary↗
PubMed1986

Effect of some proliferative and environmental factors on the toxicity of mitomycin C to tumor cells in vitro.

Mitomycin C (MC) was more toxic to EMT6 mouse mammary tumor cells in vitro under hypoxia than under aerobic conditions. This was evidenced both in survival curves defining the toxicity of treatment with a constant dose of MC given for different periods of time and in survival curves defining the effect of a 1-hr treatment with different concentrations of MC. Cultures preincubated for different periods from 1 to 6 hr in hypoxia all had similar MC sensitivities. In contrast, cultures preincubated in hypoxia for 4 hr then "reoxygenated" before MC treatment had the same sensitivities as cultures which had never been hypoxic. This shows that the oxygenation at the time of MC exposure, rather than the preincubation protocol, was the parameter determining cell sensitivity. Exponentially-growing (proliferating) and plateau-phase (quiescent) cultures had similar MC survival curves; neither type of culture repaired potentially lethal damage when held for up to 24 hr in HBSS after MC treatment. The sensitivity of the cells increased as the pH of the culture medium was decreased to low values (pH 7.0-6.0), but extracellular pH had no significant effect on the cytotoxicity of MC over the physiologic range (7.0-7.4). These data suggest that differences in the metabolic characteristics of cells that are hypoxic and aerobic during MC treatment, rather than perturbations of the cell proliferation patterns, the PLDR capacity of the cells, or the extracellular pH during the hypoxic incubation, are responsible for the different sensitivities of aerobic and hypoxic cells to MC in vitro.

Animals↗
PubMed1988

Behavior and resorption of mitomycin C following multiple intravesical administrations.

Although several pharmacological data of intravesical mitomycin C (MMC) are available now, data about resorption following subsequent intravesical instillations with different instillation times are lacking. We have analyzed MMC concentrations in blood plasma and urine following eight subsequent instillations, with 0.5- and 1.0-h instillation times. The relationships between urinary pH, urinary MMC concentrations, and MMC blood plasma concentrations were determined, as well as the stability of MMC in urine at pH 5-8 at 37 degrees C. An average of 40.3 and 46.4% of the total parent drug was recovered for the 0.5- and 1.0-h instillations, respectively. Blood plasma concentrations of MMC could be measured in nearly all patients and were independent of instillation times, urine concentration, or urinary pH. Resorption of MMC and recovery was stable during eight subsequent instillations. It was demonstrated that MMC can be degradated in urine at physiological conditions (pH less than 6; 37 degrees C). However, neither an influence of prolongation of the instillation time on MMC recovery from urine, nor a significant correlation between urinary pH and urinary MMC concentrations could be demonstrated. Since MMC can be degradated at pH less than 6 within 0.5 h, buffering of instillation fluids containing MMC is recommended. Reuse of instilled MMC, therefore, cannot be advised.

Administration, Intravesical↗
PubMed1988

Cure of advanced gastric cancer by combined chemotherapy with cisplatinum, mitomycin C, and 5-fluorouracil.

A 55-year-old female, in which an unresectable Borrmann II-type gastric cancer (moderately differentiated adenocarcinoma) extending from vicinity of the cardia to the lower portion of the corpus, with direct invasion into the pancreas and extensive lymph node metastases, confirmed by laparotomy, was treated postoperatively by 3 courses of chemotherapy with cisplatinum in combination with mitomycin C and 5-fluorouracil. A complete response was confirmed by roentgenography and endoscopy, and, at 4 months after the first operation, a total gastrectomy with radical lymphadenectomy was performed successfully. Cancer cells were not detectable histologically in the stomach specimen and in all the lymph nodes removed. One year and 5 months after the second operation she is well, showing no sign of recurrence.

Adenocarcinoma↗
PubMed1982

Hepatic artery infusion with 5-fluorouracil and mitomycin-C in metastatic colorectal carcinoma phase II study.

Thirty-two patients with hepatic metastases colorectal carcinoma were treated with hepatic artery infusion (HAI) employing 5-fluorouracil (5-FU) and mitomycin-C (mito-C). Catheters were placed percutaneously via the femoral artery. Two schedules were employed: (I) 5-FU 1,200 mg/m2 IA (D1-4) and mito-C 8 mg/m2 IA (D1 + D4); (2) 5-FU 1,200 mg/m2 IA (D1-6) and mito-C 8 mg/m2 IA (D1 + D4). Courses were repeated every 4 weeks. Thirty patients with measurable disease were evaluable, 22 received schedule I and 8 patients schedule II. Complete response occurred in two patients (6.7%) and partial response in 13 patients (43.3%). Five patients (16.7%) had minimal regression. The overall response rate as 66.7%. Median survival of all patients from start of treatment was 11.2 months. Median survival of responders and nonresponders was 12.4 months and 4.6 months, respectively (P less than 0.05). No differences in response rates, duration of response, or survival was seen between the two schedules. Drug toxicity was moderate to severe, but morbidity of HAI per se was minimal. Intermittent HAI of 5-FU and mito-C is a well-tolerated treatment modality associated with few serious complications. The response rate, duration of response, and the survival is comparable to continuous HAI infusion of 5-FU or floxuridine (FUDR). As given in this study, mito-C did not appear to provide added benefit.

Adult↗
PubMed1983

Intensive sequential chemotherapy with bleomycin, Oncovin, mitomycin C, and methotrexate followed by adriamycin, cisplatin, and cyclosphosphamide in squamous cell cancer of the head and neck.

Twenty-six patients with advanced squamous cell cancer of the head and neck were treated with bleomycin, Oncovin, mitomycin C, and methotrexate (BOMM) for ten weeks. Partial and nonresponders then received adriamycin, cisplatin, and cyclophosphamide (APC) in a planned sequential program. The response rate to BOMM was 65% (19% complete remission, CR). The overall response rate to APC was 20%. Only three of eight nonresponders to BOMM could receive APC and non responded. Six of seven partial responders received APC and only one responded. One complete responder to BOMM received APC at relapse and attained a partial response. The major side effects of BOMM were mucositis and myelosuppression. Patients receiving methotrexate 60-72 hours following the bleomycin infusion had less myelosuppression than patients who were treated 36-42 hours after bleomycin. The toxicities with APC included nausea, vomiting, and myelosuppression. Including a prior series, a total of 45 patients have been treated with BOMM with a 71% response rate (69% in previously irradiated patients). Twenty-eight percent of previously treated patients achieved complete remission, and two of these patients are disease free at 31 and 37 months. Methotrexate dose-rate alteration to low dose twice weekly followed by a single dose of oral leucovorin did not improve the complete or partial response rate when compared to weekly methotrexate administration. The complete remission rate and response duration were also not improved by the planned sequential use of this cisplatin-containing regimen.

Adult↗
PubMed1985

Combination chemotherapy with mitomycin-C, cisplatin, and vinblastine in the treatment of non-small-cell lung cancer.

The drug combination of mitomycin-C, cisplatin, and vinblastine was administered to 30 patients with stage III non-small-cell lung cancer. All patients had a performance status of 50% or greater, had evaluable disease, and had not received previous chemotherapy. The overall response rate was 37% with responses seen in 7 of 18 (39%) squamous cell and 3 of 11 (27%) patients with adenocarcinoma of the lung. Mean survival was greater by 2 months in those patients with an objective response to chemotherapy (8.1 vs 5.5). Drug-associated gastrointestinal toxicity was the most common side effect observed. This three-drug combination appears to be an active regimen in the treatment of non-small-cell bronchogenic carcinoma; however, altered dosage schedules should be examined in order to decrease drug-related toxicity.

Adenocarcinoma↗
PubMed1988

Micronucleus induction in mouse and rat fetuses treated transplacentally during histogenesis with mitomycin C and 7,12-dimethylbenz(a)anthracene.

During histogenesis, mouse and rat fetuses were treated transplacentally with mitomycin C (MMC) and 7,12-dimethylbenz(a)anthracene (DMBA). The micronucleus (MN)-inducing effects of MMC were analysed in mouse fetal blood and liver; the effects of DMBA were analysed in mouse fetal and rat fetal blood and in maternal bone marrow of both species. Both test substances were clearly clastogenic during the period of development in which the embryos were analysed--i.e., MMC from gestational day 14 until day 18 in mice and DMBA on days 14 and 17 in mice and days 16 and 19 in rats. In mouse fetal liver and blood the MMC-induced MN frequencies did not vary significantly during the whole period. MMC was more effective in fetal blood than in fetal liver. DMBA-induced MN frequencies in maternal bone marrow were slightly higher in rats than in mice. Compared to maternal bone marrow, fetal MN frequencies were about four to five times higher in rats but less than two times higher in mice. Thus, rat fetuses were far more susceptible to the clastogenic action of DMBA than mouse fetuses. These results are discussed with respect to fetal development and maternal/fetal metabolism.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1987

Enhanced susceptibility of mouse embryos heterozygous for oligosyndactyly (Os/+) to mitomycin C-induced skeletal abnormalities.

The mouse mutation, oligosyndactyly (Os), results in syndactyly, muscle anomalies, and deficiency of nephrons in heterozygous animals and early embryonic lethality in homozygotes. Since the homozygous lethality results from mitotic arrest with intact spindles at the time of implantation, we have hypothesized that the heterozygous manifestations may result from impairment of cell proliferation in regions with high proliferative rates. To test this hypothesis, Os/+ and +/+ mouse embryos at 6.5 days of gestation were exposed to mitomycin C (MMC), an agent that causes a high degree of embryonic cell death which is "compensated" for by a period of rapid cell proliferation. 17.9% of MMC-treated +/+ fetuses had fused vertebrae, a significant increase over untreated fetuses, and this frequency was further increased to 33.6% in MMC-treated Os/+ fetuses. Saline treated Os/+ and +/+ fetuses showed the same low rate (0-3%) of vertebral fusion. These results indicate that Os/+ embryos have an increased sensitivity to the vertebral fusion-inducing effect of MMC at 6.5 days of gestation, a finding compatible with the hypothesis that rapid cell proliferation may be impaired in Os/+ embryos and fetuses.

Animals↗