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PubMed1983

Permeability of the rat bladder to Cisplatinum under different conditions: comparison with Mitomycin C and Adriamycin.

In 50 female Sprague-Dawley rats the absorption of Cisplatinum through the bladder wall was studied. Under different conditions, including cystitis and electrocoagulation of the bladder mucosa, the absorption was low and the measureable serum concentrations did not exceed 2.64 micrograms/ml. The influence of Tween 80--a non-ionic surfactant--on the absorption is investigated. The results are compared with those found for Adriamycin and Mitomycin C under identical conditions.

Animals↗
PubMed1983

Proliferative kinetics and mitomycin C-induced chromosome damage in Fanconi's anemia lymphocytes.

Lymphocytes from two sisters with Fanconi's anemia (FA) were studied for cell cycle kinetics, sister chromatid exchanges (SCEs), and chromosomal aberrations when they had undergone one, two, or three or more divisions in mitomycin C (MMC)-treated cultures. Lymphocytes from the parents, another sister of the probands, and a healthy unrelated adult were examined as controls. Analyses of cell cycle kinetics by the sister chromatid differential staining method revealed that the relative frequency of metaphase cells at their third or subsequent divisions was much smaller in untreated FA cultures than in normal cultures fixed at 96 h after phytohemagglutinin stimulation. These data indicate that FA cells proliferate much more slowly than normal cells. MMC treatments of FA and normal cells led to a clearly dose-related delay in cell turnover times, the duration of delay being much longer in FA than in normal cells. FA cells had about 1.4 times higher frequencies of SCEs than normal cells in both MMC-treated and untreated cultures. FA cells also showed several times higher frequencies of chromosomal aberrations than normal cells, and the frequency of chromosomal aberrations decreased through subsequent mitoses by approximately 60% in both FA and normal cells.

Adult↗
PubMed1987

Absence of interaction between furosemide and mitomycin C.

The possible interaction between furosemide and mitomycin C (MMC) was studied in five patients. The pharmacokinetics of MMC were studied using an HPLC assay. Furosemide was administered prior to, or 120 min after MMC. Furosemide did not change the pharmacokinetics of MMC, nor did it change the amount of MMC excreted in the urine. There appears to be no interaction between the two drugs.

Adult↗
PubMed1982

Patterns of exchange induced by mitomycin C in C-bands of human chromosomes. I. Relationship to C-band size in chromosomes 1, 9, and 16.

Frequencies of exchange were determined in C-bands of chromosomes 1, 9 and 16 in six normal males, and related to relative C-band area. Comparing these different chromosomes, more exchanges occurred on average in 9 than in 1 although their mean C-band sizes were similar. Chromosome 16 exchanges were fewer, both overall and relative to C-band area. Comparing the same chromosome between individuals, there was a positive correlation between relative frequency and band size in both 1-1 and 9-9 exchanges. No clear trend was observed for other exchange events. If homology is required for interchange, it cannot be dependent solely on overall C-band size. Perhaps certain DNA sequences, sensitive to mitomycin C damage, are located in part of each C-band, with less per unit area in chromosome 1 than in 9 and still less in chromosome 16. X- and U-type exchanges between chromosome 9s occurred in near equal frequencies in all individuals. If synapsis of specific, affected sequences is a pre-requisite for interchange, this observation suggests that the affected sequence in chromosome 9 is arranged in both orientations relative to the centromere.

Chromosome Banding↗
PubMed1982

Patterns of exchange induced by mitomycin C in C-bands of human chromosomes. II. High frequency of Y-Y exchange in XYY cells.

In XY cells, exchanges in the Y C-band were rare (less than 0.8%). However, in XYY cells we observed 58 Y chromosomes involved in exchange out of 208 (28%). Most were Y-Y interchanges. Therefore mitomycin C does affect Y C-bands, but subsequent interchange requires the presence of a homologue. This may be the consequence of interphase association of the homologues, or by homologous interaction of an affected DNA sequence in the two Ys. If the latter, the proposed sequence cannot be localized to proximal or distal parts of the Y C-band, as exchange points were observed in both. Also, it may be oriented in one direction in the Y, as the Y-Y exchanges which could be unambiguously classified were X-type events.

Chromosome Banding↗
PubMed1987

Relationship between clinical parameters and pharmacokinetics of mitomycin C.

Although the number of reports on mitomycin C (MMC) pharmacokinetics is increasing, data on possible relations between clinical parameters and pharmacokinetics are usually lacking. The present report concerns the results of a detailed study on this subject in 35 patients receiving MMC, either as a single agent or as a part of combination chemotherapy. MMC concentrations were determined by HPLC. T1/2 beta varied from 23 to 78 min, VD from 11 to 48 l/m2, Cl tot from 12 to 42 l/h per m2, and AUC from 138 to 1221 micrograms/h per l, confirming previously reported data. Infusion time, cholestasis, and urinary pH did not influence the pharmacokinetic data. There were no relations between other clinical data and pharmacokinetics, nor between AUC and bone marrow toxicity. An interaction between MMC and furosemide could not be excluded, but there was no interaction with other comedication. Consecutive pharmacokinetics in 6 patients showed consistent results. Because renal impairment does not alter MMC pharmacokinetics and renal excretion is not a major route of elimination, it is suggested that renal impairment does not call for dose adjustment.

Adult↗
PubMed1983

Chemotherapeutic study on Yoshida sarcoma ascites cells implanted into the glandular stomach of rats. Monotherapy with 5-fluorouracil, methyl-CCNU, mitomycin C, adriamycin, and cytosine arabinoside, and combination therapy with respective two-drug combinations.

The chemotherapeutic activity of five cytostatic drugs was investigated experimentally in monotherapy and in two-drug combinations, using Yoshida sarcoma cells implanted into the wall of the glandular stomach of Sprague-Dawley rats. In monotherapy, the antibiotic agent mitomycin C and the nitrosourea methyl-CCNU exhibited the highest cytotoxic activity in this tumor model. In combination therapy, the combination of these two drugs was superior to all the other therapeutic schemes tested. In general, the results demonstrate a marked superiority of combination therapy in comparison with monotherapy.

Animals↗
PubMed1986

The difference in pharmacokinetics of mitomycin C, given either as a single agent or as a part of combination chemotherapy.

In a previous report it was suggested that the total body clearance of mitomycin C (MMC) was different after single agent treatment compared to combination chemotherapy. This suggestion was based on recalculations to one dose level. In the present study a fixed dose of 10 mg/m2 was used. Seven patients on single agent MMC and eight on combination chemotherapy were studied. Terminal half-life varied from 25 to 78 mm, volume of distribution from 7 to 73 l/m2, total body clearance from 11 to 56 l/h per m2, and area under the plasma concentration-time curve (AUC) from 177 to 933 micrograms/h per l. Total body clearance was significantly higher and AUC significantly lower in patients on combination chemotherapy. The cause of this difference was not investigated.

Adult↗
PubMed1988

Mitomycin C-induced organ toxicity in Wistar rats: a study with special focus on the kidney.

Two studies were performed to investigate acute and chronic organ toxicity after Mitomycin C (MMC) administration in Wistar rats. Six rats received 2.5 mg/kg MMC i.p. once and were followed for 5 consecutive days. The alanine aminopeptidase (AAP)/creatinine ratio increased significantly, compared to a control group receiving saline. Four groups of rats were injected i.p. weekly for 5 weeks; 6 control rats with saline, 7 rats with 1.7 mg/kg of MMC, 7 rats with 10 mg/kg 5-fluorouracil (5-FU) and 7 rats with MMC as well as 5-FU. The latter two groups were included to study possible toxicity synergism between the two drugs. A significant decrease in AAP excretion in the MMC group, as well as a nonsignificant decrease in the MMC/5-FU group were the most remarkable observations. Light microscopy did not show renal changes, but did not show alveolar septal congestion after repeated MMC injections. It is concluded that MMC causes tubular damage in Wistar rats, with acute leakage of enzyme from the cells, followed by enzyme depletion during chronic treatment. Also MMC induces pulmonary changes in Wistar rats. To what extent these changes represent early stages of toxicity remains to be elucidated.

Alanine Transaminase↗
PubMed1989

Induction chemotherapy with cisplatinum, 5-fluorouracil, bleomycin, mitomycin C and hydroxyurea for previously untreated locally advanced squamous cell carcinomas of the head and neck.

Fifty-three patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) were treated with a combined modality treatment consisting of three cycles of induction chemotherapy before definitive surgery and/or radiotherapy. Two additional cycles of the same chemotherapy were given after local-regional therapy. The chemotherapeutic regimen included cisplatinum 100 mg/m2 on day 1, 5-fluorouracil 1000 mg/m2 as a continuous infusion on days 2-6, bleomycin 15 units i.m. on days 15 and 29, mitomycin C 4 mg/m2 i.v. on day 22 and hydroxyurea 1000 mg/m2 p.o. on days 23-27. Each cycle was repeated every 42 days. Forty-nine patients are evaluable for response. There were 37 men and 12 women, with a median age of 58 years (range 18-75 years) and performance status of 80 (range 40-90). Sixteen patients (33%) demonstrated a complete response, 20 (41%) a partial response, yielding a 74% response rate to induction chemotherapy; 12 (24%) patients had stable disease and 1 (2%) progressive disease. The actuarial survival of those patients who completed the whole treatment program was 65% at 2 years and 47% at 3 years. Toxicities included nausea and vomiting (66%). anemia (34%), leukocytopenia (54%), thrombocytopenia (22%), stomatitis (36%), diarrhea (10%), alopecia (78%), hear impairment (4%) and transient creatinine elevation (2%). The results of the present study showed that induction chemotherapy with the above regimen produced a high rate of complete responses and can be safely combined with local-regional therapy to improve local tumor control and increase disease-free survival in patients with locally advanced SCCHN.

Adolescent↗
PubMed1991

Modulation of mitomycin C-induced multidrug resistance in vitro.

A series of in vitro cytotoxicity studies were performed to achieve pharmacologic reversal of resistance to the alkylating agent mitomycin (MMC) in L-1210 leukemia cells. A multidrug-resistant (MDR), P-glycoprotein-positive cell line, RL-1210/.1 [11], was exposed to potential MDR modulators in the absence or presence of MMC. The following compounds did not reverse MMC-induced MDR: quinine, quinidine, lidocaine, procaine, dimethylsulfoxide (DMSO), dexamethasone, hydrocortisone, prednisolone, estradiol, and testosterone. Three agents were capable of reversing MMC resistance: progesterone, cyclosporin A, and verapamil. The R- and S-isomers of verapamil were equipotent, although they showed a 10-fold difference in cardiovascular potency (S greater than R). Some agents produced cytotoxic effects in MDR cells in the absence of MMC, including progesterone, quinine, and quinidine. The results suggest that R-verapamil and progesterone may have clinical utility in reversing MMC resistance in human tumors. Progesterone may be uniquely efficacious due to (a) its low toxicity in normal cells, (b) its selective cytotoxicity in MDR cells (in the absence of MMC), and (c) its ability to reverse MMC resistance in vitro. The findings also suggest that the P-glycoprotein induced by MMC differs from that induced by doxorubicin, which is highly sensitive to modulation by lysosomotropic amines such as quinine and quinidine.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1991

Inhibition of mitomycin C's aerobic toxicity by the seleno-organic antioxidant PZ-51.

Mitomycin C (MMC) is a bioreductive alkylating agent that is capable of generating oxygen radicals. Porfiromycin (PM) is an analog to MMC that generates oxygen radicals at a significantly lower level than the parent compound. Under aerobic conditions, the toxicity of MMC to EMT6 cells is 2.5-fold that of PM, whereas hypoxically the two are equitoxic. In the present studies, the protective effect of PZ-51 in combination with NAC was assessed against the dose-dependent toxicity of either MMC or PM under both aerobic and hypoxic conditions. Aerobically, the PZ-51 and NAC combination inhibited the toxicity of MMC at concentrations of between 0.25 and 2 microM but had no effect on PM toxicity. Under hypoxic conditions, the PZ-51 and NAC combination had no effect on either MMC or PM toxicity. These findings support a role for oxygen radical generation in the aerobic toxicity of MMC at clinically relevant doses.

Acetylcysteine↗
PubMed1992

In vitro antineoplastic activity of C7-substituted mitomycin C analogues MC-77 and MC-62 against human breast-cancer cell lines.

Mitomycin C (MIT-C) is one of the most potent antineoplastic agents used for the treatment of breast cancer and a wide variety of malignant tumors. However, administration of MIT-C is frequently accompanied by the delayed onset of severe myelosuppression We have synthesized a new series of MIT-C analogues that are predicted on a structure/function basis to retain cytotoxicity but exhibit decreased toxicity. These new compounds feature a sugar substitution at the N7 position. Using a series of human breast-cancer cell lines growing in vitro, we determined the structure/activity relationship of two independent N7-substituted spacers displaying the same glucopyranose moiety. N-( [(2-acetamide-3,4,6-tri-O-acetyl-2-deoxy-beta- D-glucopyranosyl)amino]carbonyl] propylmitomycin C (MC-62) contains the sugar moiety linked to MIT-C through a butanoic acid spacer. MC-62 exhibits significantly less biological potency as compared with the parent drug. In contrast, N-[4-(tetra-O-acetylglucopyranosyl)oxy]phenylmitomycin C (MC-77) contains the glucopyranose moiety linked to MIT-C through a phenolic spacer. This analogue generally exhibits greater antitumor activity in vitro as compared with either MC-62 or MIT-C. Thus, N7-substituted analogues containing sugar moieties exhibit altered biological activity, the degree of which is related to the properties/structure of the spacer.

Breast Neoplasms↗
PubMed1990

A phase II trial of mitomycin C and 5-fluorouracil as second-line therapy in advanced breast cancer.

Fifty-five patients who had relapsed or progressed from chemotherapy for advanced disease were treated with mitomycin C and 5-FU on a 6 weekly regimen. After a median of 2 cycles of therapy the overall response rate was 12% with no complete responses. Significant leucopenia but no thrombocytopenia was seen and despite the low overall response rate the regimen was tolerable and did produce responses in patients primarily resistant to Adriamycin combination chemotherapy. Low overall activity indicates the need for more effective second line treatment.

Adult↗
PubMed1995

Conversion of mitomycin C to 2,7-diaminomitosene and 10-decarbamoyl 2,7-diaminomitosene in tumour tissue in vivo.

The progress of mitomycin C (MMC) bioreduction was studied in vivo in the rat Sp 107 mammary carcinoma after intra-tumoural injection of either 100 micrograms or 1 mg. 2,7-Diaminomitosene (2,7-DM) was utilised as a primary bioreductive metabolite and 10-decarbamoyl 2,7-diaminomitosene (DC 2,7-DM) served as a secondary bioreductive metabolite, both of which were measured by high-performance liquid chromatography. 2,7-DM and DC 2,7-DM were produced rapidly, achieving close to their maximal concentrations at the earliest time point studied [5 min]. 2,7-DM was cleared rapidly from the tumour with apparent half-lives of 5 and 35 min after the low and high drug doses, respectively. DC 2,7-DM had a longer apparent half-life of 130 min at the higher dose but, as compared with 2,7-DM, was only a minor metabolite [the area under the curve (AUC) of 2,7-DM was 5.6-fold that of DC 2,7-DM]. At the lower drug dose, DC 2,7-DM was not detectable. Rapid formation and disappearance of bioreductive metabolites of MMC may account for the failure of previous studies to detect these products in vivo.

Animals↗
PubMed1991

High mitomycin C concentration in tumour tissue can be achieved by isolated liver perfusion in rats.

To enable the treatment of hepatic metastasis with higher, theoretically more effective, doses of systemically toxic anticancer drugs, an isolated liver perfusion (ILP) technique was developed in WAG/Ola rats. First, in a toxicity study the maximally tolerated dose (MTD) of mitomycin C (MMC) was determined for a 25-min ILP and for hepatic artery infusion (HAI) after the administration of a bolus dose. The MTD in the ILP setting (4.8 mg/kg) was 4 times that using HAI (1.2 mg/kg). Subsequently, in a rat colorectal hepatic-metastasis model, concentrations of MMC in tumour, liver, plasma and perfusate were measured during a 25-min ILP to investigate the expected pharmacokinetic advantage of ILP. The mean plasma level determined after ILP (1.2 as well as 4.8 mg/kg MMC) was significantly lower (P less than 0.001) than that obtained following HAI. This may explain both the absence of severe systemic toxicity and the higher MTD in ILP-treated groups. No significant difference in mean tumour and liver tissue concentrations of MMC were found when the groups treated with 1.2 mg/kg drug via HAI vs ILP were compared. The mean MMC concentration in tumour tissue was significantly higher (almost 5 times; P less than 0.05) in rats treated by ILP with the MTD (4.8 mg/kg) than in those treated via HAI with the MTD (1.2 mg/kg). ILP of MMC can be safely performed using a dose 4 times higher than the MTD in the HAI setting, leading to an almost 5-fold concentration of MMC in hepatic metastasis. ILP of MMC may therefore represent a promising therapy for metastasis confined to the liver.

Animals↗
PubMed1991

Mitomycin C, teniposide, and cisplatin combination chemotherapy for advanced non-small-cell carcinoma of the lung.

A total of 45 patients with advanced non-small-cell lung carcinoma were treated with a combination of cisplatin, teniposide, and mitomycin C. Most subjects exhibited good prognostic factors (performance status, 0-1; minimal weight loss; locoregional disease). Toxicity consisted mainly of myelosuppression and nausea and vomiting. Four patients died of sepsis due to chemotherapy-induced leukopenia. The response rate was 39.5%, with no complete responses being observed; the median duration of partial responses was 231 days and median survival was 243 days. Although the response rate and durations of both response and survival were comparable with those obtained using other cisplating-containing regimens, myelotoxicity was rather pronounced in the present study. Further studies of teniposide in this type of combination are not warranted.

Adult↗