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Chemical stability of the antitumor drug mitomycin C in solutions for intravesical instillation.

The chemical stability of the antitumor drug mitomycin C has been investigated by using a stability indicating high performance liquid chromatographic assay. The stability tests were performed in different media and under different conditions which are important for the clinical urology practice in the intravesical chemotherapeutic treatment of superficial bladder cancer. It is concluded that mitomycin C can be dissolved in Water for Injection to a concentration of 30 or 40 mg/50 mL. These solutions are stable for four days at ambient temperature and in the dark. Storage of solutions with a concentration of 30 mg/50 mL are stable for four days in the refrigerator but higher concentrations show precipitation after one day storage at 4 degrees C. Dissolution and storage in 0.9% sodium chloride solution or phosphate buffer pH 7.4 is not recommended because in these, media degradation and/or precipitation occur.

Administration, Intravesical↗
PubMed1990

Eosinophilic cystitis and allergy to mitomycin-C.

Eosinophilic cystitis appears to have an allergic origin to different substances causing an immunological reaction. Up to now it was unknown that Mitomycin-C could cause this reaction. We present 6 cases of eosinophilic cystitis induced by Mitomycin-C analysing their clinical and pathological characteristics.

Aged↗
PubMed1986

Cellular interaction and in vitro antitumor activity of mitomycin C-dextran conjugate.

Cellular interaction and in vitro antitumor activity of a polymeric prodrug of mitomycin C (MMC), mitomycin C-dextran conjugate (MMC-D), were studied in relation to its physicochemical characteristics. MMC-D with cationic and anionic charges were examined. The cationic MMC-D was synthesized using a spacer, epsilon-aminocaproic acid and dextrans with molecular weights of 10,000, 70,000, or 500,000 [MMC(C6)Dcat]. The anionic MMC-D was synthesized using 6-bromohexanoic acid as a spacer and dextran with a molecular weight of 70,000 [MMC(C6)Dan]. Cellular adsorption was determined by measuring the concentration of the drug in the medium after incubation with three tumor cell lines, Ehrlich ascites carcinoma, L1210 leukemia, and AH66 ascites hepatoma cells. MMC(C6)Dcat was adsorbed more readily than MMC or MMC(C6)Dan on the tumor cell surface by an electrostatic force. The percentage of adsorption remained almost constant during the course of incubation and no significant difference was observed between the incubation at 4 degrees C and that at 37 degrees C. A corresponding increase in the amounts of MMC(C6)Dcat adsorbed on with higher molecular weights was noted, which conformed to Langmuir's adsorption isotherm. In vitro antitumor activity was evaluated using L1210 and EAC cell culture systems and human tumor colony forming assay. MMC(C6)Dcat showed growth inhibition essentially equal to that of MMC in continuous drug exposure experiments. In a 1-h drug exposure experiment, MMC(C6)Dcat with a molecular weight of 70,000 or 500,000 was more active than MMC, and a good correlation was observed between the effects of MMC(C6)Dcat and the extent of cellular interaction. These results show that cellular interaction played an important role in the manifestation of the antitumor effect of MMC-D and that these phenomena are governed by the physicochemical properties of macromolecular prodrugs, such as electric charge and molecular weight.

Adsorption↗
PubMed1987

Disposition characteristics of mitomycin C-dextran conjugate in normal and tumor-bearing muscles of rabbits.

Disposition characteristics of the macromolecular prodrug of mitomycin C (MMC), mitomycin C-dextran conjugate (MMC-D), in normal and tumor (VX2 carcinoma)-bearing rabbit thigh muscles were studied using the in situ vascular perfusion technique. Three types of cationic MMC-D (MMC-Dcat) and two types of anionic MMC-D (MMC-Dan) with different carrier molecular weights were used. After bolus arterial injection in normal muscles, 83-96% of injected MMC-D was recovered in the venous outflow regardless of the carrier size or charge, whereas less than 60% of MMC was recovered in the same system. By applying statistical moment analysis to the outflow pattern of these drugs, pharmacokinetic parameters representing their disposition characteristics were obtained. Smaller intrinsic clearance (CLint) and distribution volume (V) were noted for MMC-D than for MMC, indicating low extravascular diffusion of MMC-D. In the tumor-bearing muscle, blood contamination from other parts of the body increased and a shortage of flow recovery due to the neovascularization of the tumors occurred. The disposition parameters of MMC-Dcat with a molecular weight of 500,000 (T-500) indicated some tissue distribution and sequestration in the tumor preparation. After constant infusion of [14C]MMC-D (T-500) for 4 h, tissue radioactivity concentrations were determined in various tissues. A higher radioactivity was observed in the viable region of the tumor and the lymph node compared with the normal muscle tissue and the necrotic region of the tumors. 131I-Labeled human serum albumin also gave similar results. In conclusion, higher tumor localization of antitumor agents may be made possible by the application of macromolecular prodrugs.

Animals↗
PubMed1989

[Intraoperative chemotherapy against peritoneal dissemination of gastric cancer with intraperitoneal activated carbon particles adsorbing mitomycin C].

For prevention and therapy of peritoneal dissemination, a new dosage from (MMC-CH) comprising carbon particles adsorbing mitomycin C was given to 44 patients (the MMC-CH group) undergoing gastrectomy for gastric cancer, of which advancing stage was classified into the category of H0, and S2 or S3, and P0, P1, P2 or P3 according to the General Rules for the Gastric Cancer Study. MMC-CH, principally at 50 mg person in terms of mitomycin C was administered intraperitoneally before the surgical wound was closed. Historical control group was composed of 53 patients not given MMC-CH, who underwent gastrectomy for gastric cancer in the same advancing stage as those of the 44 patients. There was statistically no significant difference of age, sex, depth of infiltration, macroscopically and microscopically defined progression of lymph-nodal metastases, between the MMC-CH group and the historical control group. The survival rate of the overall patients, and each group of the patients with the lesion defined as P0, P1, P2, or P3 was compared with Kaplan-Meier's method between the MMC-CH group and the historical control group. In the MMC-CH group, the survival rates of the overall patients and the patients with P0, P1, or P2 lesion were statistically significantly higher than those in the historical control group. However, the rate of the P3 patients in the MMC-CH group was statistically significantly lower than in the historical control group.

Adsorption↗
PubMed1989

[Blood levels of mitomycin C in patients given by various routes of administration].

Twenty mg of mitomycin C was administered to patients with colo-rectal cancer through various routes of administration. The values of pharmacokinetic parameters were as follows Intra-arterial administration (3 patients with rectal cancer): T1/2 alpha 8.4 min, T1/2 beta 63.8 min, maximum concentration (5 min after ia injection) 0.83 microgram/ml, AUC0-120 25.0 micrograms/ml/min. Intra-portal administration (7 patients with colon cancer): T1/2 alpha 6.1 min, T1/2 beta 61.0 min, maximum concentration (5 min after iv.) 0.75 microgram/ml, AUC0-120 25.3 micrograms/ml/min. Intra-peritoneal administration (14 patients with colon cancer): maximum concentration (20-30 min after i.p.) 0.23 microgram/ml, AUC0-120 21.1 micrograms/ml/min. Intra-pelvic administration (7 patients with rectal cancer): maximum concentration (20-30 min after i.p.) 0.06 micrograms/ml, AUC0-120 7.3 micrograms/ml/min. The reduction curve of intra-arterial administration closely resembles to that of intra-portal administration. Maximum blood level and AUC of intracavitary administration were relatively low compared with those of administration into blood vessels. Bone marrow suppression was seen in patients given mitomycin C into blood vessels and wound healing disturbance such as anastomotic leakage were noted in patients by intra-cavitary administration.

Adult↗
PubMed1989

[Intraoperative chemotherapy with intraperitoneal activated carbon particles adsorbing mitomycin C against peritoneal dissemination of gastric cancer].

A new form of dosage (MMC-CH) was composed of activated carbon particles adsorbing mitomycin C. Intraperitoneal administration of MMC-CH was tested clinically for prophylactic and therapeutic effects on peritoneal carcinomatosis of gastric cancer. The criteria of MMC-CH's administration were equal or less than 70 years old, more than 40 kg in body weight, no disfunction of liver and kidney, no particular findings in electrocardiography, S2 or S3 in the grade of serosal invasion, P0, P1, P2 or P3 in the grade of peritoneal dissemination, according to the General Rules for the Gastric Cancer Study in Surgery and Pathology by the Japanese Research Society for Gastric Cancer. MMC-CH was given to 44 patients undergoing gastrectomy for gastric cancer in our department from 1985 to 1988. The 44 patients were composed of 12 patients with P0 findings (P0 patients), 8 patients with P1 findings (P1 patients), 12 patients with P2 findings (P2 patients), and 12 patients with P3 findings (P3 patients). MMC-CH at 50 mg/person in terms of mitomycin C was administered intraperitoneally before the operation wound was closed. Fifty-seven patients in our department from 1983 to 1987 for whom the same criteria were applicable and did not receive MMC-CH therapy, served as the control group. The 57 patients were composed of 23 P0 patients, 21 P1 patients, 10 P2 patients, and 3 P3 patients. There was statistically with chi 2 test no significant difference of age, sex, depth of infiltration macroscopically and microscopically defined progression of lymph-nodal metastases between the MMC-CH group and the control group. Survival rate was calculated with Kaplan-Meier's method in the overall patients in each of the MMC-CH group or the control group. The overall survival rate in the MMC-CH group was statistically significantly (p less than 0.01-0.05) higher from day 460 to day 552 and from day 736 to day 800 than that in the control group. Next, the patients were classified into two subgroups, namely the subgroup composed of P0 patients and the subgroup composed of P1, P2, and P3 patients, in order to examine each of the MMC-CH's prophylactic effects on subsequent dissemination or its therapeutic effects on established dissemination. Survival rate was calculated with Kaplan-Meier's method in the two subgroups through the same procedures used for the overall survival rate.(ABSTRACT TRUNCATED AT 400 WORDS)

Absorption↗
PubMed1989

Cis-platinum and mitomycin-C in treatment of recurrent, metastatic, or residual uterine cervical cancer post radiation.

Fifteen patients with recurrent, metastatic, or residual cervical cancer post radiotherapy were treated by combined cis-platinum 40 mg/m2 IV and mitomycin-C 30 mg/m2 IV in day 1, repeated every 4 weeks for 3-5 cycles. The maintained therapy was performed by mitomycin-C 2 mg/day orally for 7 days, every 4 weeks for 6 cycles. Six of 15 patients (40%) showed complete remission and are alive without disease after a follow-up period of 5-41 months; 3 patients (20%) with partial remission are alive with disease after a follow-up period of 8-12.5 months; 6 patients (40%) with no remission expired with a survival time of 3-6 months. Severe anemia and leukopenia (grade 3-4) were seen in 26.66 per cent. Thrombocytopenia grade 4 was seen in 13.33 per cent of cases. Nausea and vomiting occurred in almost all patients. There were no problems with hepatotoxicity, nephrotoxicity, or ototoxicity.

Adenocarcinoma↗
PubMed1989

Phase I trial of mitomycin C immunoconjugates cocktails in human malignancies.

Nineteen patients with refractory solid malignancies received individualized combinations of mitomycin C conjugated murine monoclonal antibodies selected by immunohistochemical and flow cytometric screening of tumor specimens. There were no responses in this Phase I study. Thrombocytopenia precluded escalation above a mitomycin C dose of 60 mg per treatment cycle. Preclinical, clinical, and toxicity experiences with this investigational approach to the treatment of cancer are discussed.

Adult↗
PubMed1989

[Effect on immunological response of host by mitomycin C adsorbed into activated carbon particles (MMC-CH) in mice].

Mitomycin C adsorbed onto activated carbon particles (MMC-CH) has been administered intraperitoneally for C57BL/6 mice. The weight of the spleen and thymus of the mice given MMC-CH was decreased lesser than those of the mice given mitomycin C aqueous solution (MMC-AQ). The number of peritoneal exudate cells (PEC) in the mice given MMC-AQ was decreased remarkably on 1st day after MMC-AQ administration and recovered within normal range on the 7th day. On the other hand, the number of PEC in the mice given MMC-CH was increased remarkably on the 1st day and then gradually decreased to normal range on the 7th day. Reactivity of spleen cells by Con A was inhibited in the spleen cells from the mice given MMC-AQ more than those from the mice given MMC-CH. Fifth percent lethal dose was 8.0mg/kg in the mice given MMC-AQ, and 18.2mg/kg in the mice given MMC-CH.

Absorption↗
PubMed1989

Significance of antigen, drug, and tumor cell targets in the preclinical evaluation of doxorubicin, daunorubicin, methotrexate, and mitomycin-C monoclonal antibody immunoconjugates.

We tested drug monoclonal antibody immunoconjugates in vitro in 72 h 3H-thymidine assays and in vivo in athymic mice bearing human tumor xenografts of the same target cells. Experimental arms included control, monoclonal antibody, drug, drug + antibody, the test immunoconjugate, and a negative control immunoconjugate with an equivalent molar amount of drug for in vitro experiments, and the amount of drug conjugated to 500 micrograms of antibody in the animal experiments. Monoclonal antibodies included T101, an IgG2a that reacts with a rapidly modulating antigen, 9.2.27, an IgG2a that reacts with a slowly modulating antigen, and ME7, an IgG1 that reacts with a slowly modulating antigen. Cells used in testing included MOLT-4 (T lymphoma), 8392 (B lymphoma), and M21 (melanoma). Drugs tested were doxorubicin, daunorubicin, methotrexate, and mitomycin-C. M21 cells were resistant to daunorubicin in vitro but were inhibited by the 9.2.27 daunorubicin immunoconjugate. T101, 9.2.27, and ME7 cis-aconitate anthracycline immunoconjugates and mitomycin-C-glutarate immunoconjugates were specifically cytotoxic only for antigen positive cells in vitro and were superior to free drug in vivo. These results confirm that antigen specific-cytotoxic drug immunoconjugates can be produced that are superior to the same dose of free drug. However, each monoclonal antibody drug target system is unique and must be well-characterized for appropriate interpretation of data.

Animals↗
PubMed1985

A comparison of three chemotherapeutic regimens in the treatment of advanced pancreatic and gastric carcinoma. Fluorouracil vs fluorouracil and doxorubicin vs fluorouracil, doxorubicin, and mitomycin.

Three hundred five patients with advanced pancreatic and gastric carcinoma were randomly assigned to treatment with fluorouracil, fluorouracil plus doxorubicin (Adriamycin) (FA), or fluorouracil plus doxorubicin plus mitomycin (mitomycin C) (FAM). All regimens were equivalent with regard to patient survival. There is no reasonable likelihood that either the FA or FAM regimen could produce a meaningful survival advantage over fluorouracil alone. Interval to disease progression, objective response rates, and palliative effects (improved performance, body weight, or symptoms) were essentially equivalent among the three regimens. With regard to toxicity, the FAM regimen produced more anorexia, nausea, vomiting, leukopenia, thrombocytopenia, and cumulative bone marrow suppression. Fluorouracil alone produced more stomatitis and diarrhea. Because of a failure to produce improved survival or palliation, unrewarded toxicity, and excessive cost, neither the FA nor FAM regimen can be recommended for the treatment of advanced pancreatic or gastric cancer.

Adenocarcinoma↗
PubMed1989

[5-Fluorouracil, adriamycin, and mitomycin C (FAM) combination chemotherapy in adenocarcinoma of the parotid gland].

An adenocarcinoma of the parotid gland is a rare tumor and little is known about the efficacy of chemotherapy as a method of treatment. Four patients with a metastatic, or recurrent adenocarcinoma of the parotid gland were treated with a combination chemotherapy consisting of 5-fluorouracil, adriamycin, and mitomycin C (FAM): 5-fluorouracil 330-500 mg/m2, d1-3, q3w or tegafur 400-600 mg/m2 p.o. adriamycin 30-40 mg/m2 q3w, and mitomycin C 3-10 mg/m2, q1-2w. One patient with a lung metastasis showed a good partial response lasting for 19 months and another patient who was resistant to CDDP plus the adriamycin combination, having a lymph node, bone, and bone marrow metastases, had a partial response lasting for 31 months. Results have indicated that adriamycin is one of the effective therapeutic drugs and that FAM combination chemotherapy can provide some efficacy against a parotid cancer.

Adenocarcinoma↗
PubMed1988

Neoadjuvant mitomycin C, cisplatin, and infusion vinblastine in locally and regionally advanced non-small cell lung cancer: problems and progress from the perspective of long-term follow-up.

Thirty-one patients with inoperable, locally and regionally advanced non-small cell lung cancer (NSCLC) were treated with mitomycin C, cisplatin, and continuous-infusion vinblastine (M-PV) in combination with thoracic irradiation (26 patients) or attempted surgical resection following M-PV (five patients). The total response rate to primary M-PV was 73%, and four of five patients undergoing thoracotomy following M-PV were completely resected. With a median follow-up in excess of 4 years, the median survival with neoadjuvant M-PV is 19 months, and the 4 and 6 year actuarial survivals are 31% and 26%, respectively. In contrast, in 42 individuals with equivalent prognostic factors concurrently treated with irradiation alone, the median survival is 8 months, the 4 and 6 year survivals are 6% and 3%, respectively. Although lung injury was the major toxicity encountered with neoadjuvant therapy, the incidence and severity of that complication could be significantly reduced with administration of dexamethasone, 10 to 12 mg IV X 1, before each dose of mitomycin C; a maximum of three courses of primary M-PV before consolidation with radiation therapy (RT) or surgery; and serial diffusion capacity (DLCO) measurement as a potential gauge of impending toxicity with further therapy.

Aged↗
PubMed1985

DNA strand scission by enzymatically reduced mitomycin C: evidence for participation of the hydroxyl radical in the DNA damage.

Phage DNA, as well as plasmid and mammalian DNA's, were exposed to a superoxide and hydroxyl radical-generating system containing NADPH-cytochrome P-450 reductase and mitomycin C, both with and without added Fe3+-ADP, in phosphate buffer at pH 7.5. The generation of superoxide (O2-.) and hydroxyl (.OH) radicals in the system was demonstrated by using ESR spectrometry with N-tert -butyl-alpha-phenylnitrone (PBN) as a spin trapping agent. Only the lambda DNA isolated after exposure to the O2-./.OH-generating system containing many lower molecular weight DNA fragments indicating DNA strand breaks. This breakage was completely inhibited by a .OH radical scavenger (sodium benzoate) and by catalase, but only slightly by superoxide dismutase. Thyroid and plasmid DNA's were both cleaved when exposed to the O2-./.OH-generating systems. It is suggested that the mechanism of DNA scission by mitomycin C described here closely resembles that induced by the anthracycline drugs.

Animals↗
PubMed1986

[Induction of activated macrophages by intraperitoneal injection of mitomycin C in mice and rats].

The local cellular response induced by i.p. injection of mitomycin C (MMC) was studied in C3H/HeN mice and ACI/N rats. MMC-induced peritoneal macrophages showed the maximum in vitro tumoricidal activity against 125I-UdR-labeled syngeneic tumor target cells 4 to 7 days after the i.p. injection of MMC at a single dose of 3 mg/kg and 1 mg/kg in mice and rats, respectively. The tumoricidal activity was dependent on the dose of mitomycin C injected and it was alos detectable against allogeneic and xenogeneic tumor target cells. In addition, these tumoricidal macrophages were found to have augmented functions of 2-deoxy-D-glucose incorporation and phagocytosis. Additional experiments excluded the possibility that the tumor cell cytolysis was the result of direct cytotoxicity of MMC that might have been incorporated into the peritoneal macrophages or of nutrient depletion in the medium during the cytolysis assay. Although the mechanism by which MMC injected i.p. induced the tumoricidal macrophages locally remained undetermined, in vitro production of macrophage-activating factor (MAF) from splenocytes cultured with concanavalin A was enhanced remarkably, following exposure of the spleen to MMC in vivo or in vitro, indicating the involvement of lymphokine in the induction of tumoricidal macrophages by MMC. Among other anticancer drugs, which were used at a dose of three-fifths of LD50, only adriamycin (7.5 mg/kg) was capable of inducing tumoricidal macrophages. A better understanding of the effect of anticancer drugs on macrophage tumoricidal activity may be useful in designing more effective local chemotherapy for cancerous peritoneal effusions.

Animals↗
PubMed1987

Mitomycin C induced chromosomal aberrations and sister chromatid exchanges (SCEs) in lymphocytes of patients with precancerous and cancerous lesions of the uterine cervix.

Baseline and mitomycin C (MMC)-induced chromosomal aberrations and sister chromatid exchanges (SCEs) in blood lymphocytes of patients with cervical precancerous and cancerous lesions and normal women were studied. The baseline frequency of chromosomal aberrations and SCEs revealed a significant increase in higher grades of precancerous (moderate and severe dysplasias) and cancerous lesions compared to those of controls. The MMC-induced chromosomal aberrations and SCEs did not show any differential response in the different groups studied. The results thus indicate that chromosomal instability as observed in precancerous and cancerous lesions is not associated with their sensitivity to mitomycin C.

Chromosome Aberrations↗
PubMed1987

[Pulmonary fibrosis following instillation of mitomycin C in the urinary bladder].

Intravesical prophylaxis against recurrence of bladder carcinomas using mitomycin C has proved to be an effective treatment with few side effects. No side effects involving the lungs have so far been observed with systemic administration; with intravesical use, however, this is not the case. We report a 32-year-old man in whom pulmonary interstitial fibrosis occurred after intravesical instillation of mitomycin C. The clinical picture, including the therapy, and the differential diagnosis and practical consequences are all discussed.

Administration, Intravesical↗