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PubMed1985

Antitumor activity and toxicity in animals of BMY-25282, a new mitomycin derivative.

BMY-25282, 7-N-(dimethylamino methylene)mitomycin C, is one of a novel series of amidino mitomycin derivatives. Some of these were discovered as intermediates in a synthetic program being conducted to find improved procedures for modifying the structure of mitomycin C (MMC). Markedly superior in vivo antitumor effects have been observed with BMY-25282 compared to MMC in initial tests against i.p.-implanted P388 leukemia and B16 melanoma. When administered i.v. to mice bearing s.c. B16 melanoma, BMY-25282 was also superior to MMC. The derivative was fully active against a line of L1210 leukemia which was partially resistant to MMC treatment but had little or no activity against a line of L1210 fully resistant to MMC. It is also 2 to 4 times more potent than MMC based on a comparison of doses required to achieve optimum antitumor effects. The superior antitumor efficacy of BMY-25282 over MMC against both i.p. and s.c. B16 melanoma was maintained when the drug was given in pluronic acid formulation. Against P-388 leukemia, however, the efficacy of the drugs was equivalent when BMY-25282 was administered in the pluronic vehicle. In an in vitro clonogenic assay involving freshly explanted human tumors, BMY-25282 was consistently more potent in cytotoxic effects than MMC. With human colorectal carcinoma samples, BMY-25282 was 13.8 times more potent than MMC. The i.v. 50% lethal dose values of BMY-25282 and MMC in C57BL/6 X DBA/2 F1 mice were 2.1 mg/kg and 8.6 mg/kg, respectively. Leukopenic effects of the drugs in mice were comparable at doses up to their respective 50% lethal dose values. Hematology studies in ferrets revealed a similar pattern of depression and recovery of lymphocytes, neutrophils, and platelets for BMY-25282 and MMC; however, with BMY-25282 there was earlier recovery of platelet counts. BMY-25282 is being further developed toward possible clinical trial.

Animals↗
PubMed1983

[Combination chemotherapy of advanced gastric cancer with adriamycin, mitomycin C, and ftorafur].

Thirty patients with advanced gastric cancer were treated with a combination chemotherapy consisting of adriamycin 20-30 mg/m2 iv day 1 q3wks, mitomycin C 2.7-4 mg/m2 iv day 1 weekly, and ftorafur 267 mg/m2 po b.i.d. daily. Five (28%) of 18 patients with measurable lesions achieved partial responses with a median duration of 2 months ranging 1.5 to 8 months. The median survival time from initiation of the chemotherapy was 4 months in responders, and 5 months in non-responders, respectively. The response rate did not correlate with the various baseline parameters including initial performance status, resectability of the primary tumor, histologic differentiation of the tumor, and prior chemotherapy. Gastrointestinal and hematologic toxicities were mild and well manageable. Cumulative thrombocytopenia and renal damage probably due to mitomycin C, were seen in 5(17%) and 2(7%) patients, respectively. Clinical cardiotoxicity induced by adriamycin was observed in one patient. The result indicated that the enhancement of antitumor effect with a combination of adriamycin, mitomycin C, and ftorafur for advanced gastric cancer was not significantly remarkable as expected. Thus, further study will be required for obtaining more favorable result.

Adenocarcinoma↗
PubMed1983

Pharmacokinetics of mitomycin C in patients receiving the drug alone or in combination.

We have characterized plasma pharmacokinetics in 30 patients receiving mitomycin C (mitomycin) in doses ranging from 6 to 20 mg/m2 by iv bolus injection, either alone or in combination with other chemotherapeutic drugs. Plasma elimination of the drug was described by a two-compartment model in all but three cases, giving mean values for alpha-half-life of 8.2 mins, beta-half-life of 51.8 mins, and total body clearance of 332.9 ml/min/m2. The mean urinary excretion was 8.1% of the total dose administered. We did not detect alterations in pharmacologic parameters related to liver dysfunction, dose of mitomycin, and concomitant administration of other cytotoxic drugs.

Adult↗
PubMed1983

[Genetic control of the protective effect of spermidine in Escherichia coli cells as affected by mitomycin C].

The lethal action of mitomycin C and the effect of mutual treatment with mitomycin C and spermidine on Escherichia coli were studied. DNA repair in cells treated with mitomycin C was shown to have some differences, as compared to that of UV-induced pyrimidine dimers. The presence of the additive sbcB mutation increases the resistance of wild-type bacteria as well as of recBrecC and recF mutants to the lethal action of mytomicin C. Preliminary treatment of bacteria with spermidine increases resistance to the lethal action of the mutagen in wild-type bacteria as well as uvrB, recBrecC and sbcB strains. However, no such effect was observed in recF, recFsbcB and uvrE strains. The data suggest that the protective action of spermidine may be connected with stimulation of RecF-pathway of postreplication repair.

Antibiotics, Antineoplastic↗
PubMed1983

[In vitro antitumor activity of 7-N-(p-hydroxyphenyl)-mitomycin C (KW-2083) against cultured bronchogenic carcinoma cells (PC-7)].

The in vitro antitumor activity of 7-N-(p-hydroxyphenyl)-mitomycin C (KW-2083) against cultured bronchogenic carcinoma cells (PC-7) was compared with that of mitomycin C, using a 3H-thymidine uptake assay. The uptake of 3H-thymidine into PC-7 cells was well correlated with the cell concentration under 1 X 10(5)/ml. It was more strongly inhibited after incubation of the PC-7 cells with KW-2083 than with mitomycin C at the concentration of 0.5, 2.5 and 10 micrograms/ml for 20 and 60 min. The placebo of KW-2083 containing HCO-60 and propyleneglycol showed no effect on the uptake of 3H-thymidine by PC-7 cells.

Carcinoma, Bronchogenic↗
PubMed1983

Survival and induction of recA protein in mitomycin C-treated Escherichia coli rec, lex, or uvr strains.

The capability to synthesize recA protein has been tested for Escherichia coli treated with mitomycin C. recA protein was assayed using an immunoradiometric assay (Paoletti, C., Salles, B., and Giacomoni, P. U. (1982) Biochimie 64, 239-246). Mitomycin C-treated wild type E. coli can express recA gene in a similar quantitative fashion, independently of the growth media used in this work; glucose did not inhibit induction of recA protein in cells growing in synthetic media. Wild type E. coli recovering from energy starvation displays a similar qualitative capability to induce the synthesis of recA protein independently of the stage of growth at which the cells are treated with the drug. At midexponential phase, the cells appear to have an enhanced capability to synthesize recA protein. The relationship between survival and capability to synthesize recA protein was explored for E. coli lex, rec, and/or uvr mutants, after treatment with mitomycin C. A good correlation was found, except for a recB mutant and for an ethidium-sensitive strain, both able to produce as much recA protein as the wild type but 100-fold more sensitive to the drug. A similarly satisfactory correlation was found when plotting the survival after UV irradiation versus the capability of synthetizing recA protein with the exception of an uvrA strain and of a lexA strain.

Antibiotics, Antineoplastic↗
PubMed1983

Specificity of antisera produced against mitomycin C.

The specificity of antisera produced in rabbits for use in mitomycin C (MMC) enzyme immunoassay has been examined employing competitive experiments using several mitomycin analogs and the chemically or biologically degraded preparations of MMC. These studies demonstrate that the antiserum distinguished alterations in the chemical structure of the molecule, showing decreased immunoreactivity with mitomycin A (7.8%) and B (0.78%). On the other hand, porfiromycin and acetyl MMC (Ac-MMC), which commonly possess the substituted groups (methyl and acetyl groups, respectively) at the aziridine ring, showed enhanced reactivity with the antiserum (about two times and ten times as compared to the parent MMC, respectively), suggesting that the antigen used for antibody production was the MMC acylated at the imino group of the aziridine ring. The values of the chemically or biologically degraded preparations of MMC quantified by this enzyme immunoassay were in good agreement with those of the remaining nonreacted MMC measured spectrophotometrically, thus indicating that the anti-MMC antiserum hardly cross-reacted with these degradation products.

Animals↗
PubMed1984

Experimental and clinical activity of mitomycin C and cis-diamminedichloroplatinum in malignant mesothelioma.

Little information is available regarding the effectiveness of chemotherapeutic agents in malignant mesothelioma. Human malignant mesothelioma specimens from two patients were successfully transplanted and maintained in homozygous nude mice. Screening of chemotherapeutic agents revealed that cisplatin was the most active single agent in one line, and mitomycin C in the other. The combination of mitomycin C and cisplatin, however, was the most effective regimen for both lines of xenografted human mesothelioma. Based on these results in nude mice, a clinical trial of mitomycin C and cisplatin was undertaken. Four of 12 patients showed objective response (one complete and three partial). These clinical results support the usefulness of the nude mouse model for malignant mesothelioma.

Aged↗
PubMed1984

Development and application of a sensitive enzyme immunoassay for 7-N-(p-hydroxyphenyl)mitomycin C.

An antibody specific for 7-N-(p-hydroxyphenyl)mitomycin C (M-83) was developed and used in a simple and sensitive enzyme immunoassay for detection of this anticancer drug in serum. The imino group of M-83 was covalently coupled to mercaptosuccinyl groups introduced into bovine serum albumin with a cross-linker, N-maleoylaminobutyric acid. The resulting conjugate was then used for the production of a specific antibody to M-83 in rabbits. Enzyme labeling of M-83 was performed using beta-D-galactosidase (EC 3.2.1.23) via m-maleoylbenzoic acid. Antibody production was of sufficiently high titer in rabbits to allow the development of a highly sensitive enzyme immunoassay for the free drug which accurately measures 15 pg of M-83 per assay tube. This assay was monospecific to M-83 and showed almost no cross-reactivity with a variety of other mitomycin analogues (mitomycin A, B, and C; porfiromycin; and acetylmitomycin C). Using this assay, preliminary pharmacokinetic study was undertaken using serial serum samples obtained from a patient who received the drug i.v., revealing a biphasic fashion of the kinetics, with an alpha-serum half-life of 9.7 min and a beta-serum half life of 80 min. An i.v. injection of M-83 into rats and assay of serum concentration revealed a similar biphasic response with an alpha-serum half-life of 8.3 min and a beta-serum half-life of 62 min.

Antibodies↗
PubMed1984

Effects of total body irradiation followed by bone marrow transplantation on the disposition kinetics of mitomycin-C in the rat.

The effects of total body irradiation followed by bone marrow transplantation on the disposition kinetics of intravenously-administered mitomycin-C have been studied in the Wistar-Furth rat. Five test animals received total body irradiation (1000 rads) followed by intravenous administration of 3 X 10(8) bone marrow cells per kg body weight. Five control animals were sham-irradiated and received an equal volume of blank suspension medium. One day after these treatments, each rat received mitomycin-C (10 mg/kg) by rapid intravenous injection and serial blood samples were obtained. Serum mitomycin-C concentrations were measured by high performance liquid chromatography and pharmcokinetic parameters were calculated after NONLIN analysis of data. Smaller total body clearances in test animals were probably due to radiation-induced inhibition of microsomal enzyme activity. Reduced volumes of distribution were observed in test animals although the reason for this is unclear. Future studies should assess the clinical significance of these results.

Animals↗
PubMed1982

[Phase I study of KW2083 7-N-(p-hydroxyphenyl) mitomycin C].

KW2083 7-N-(p-hydroxyphenyl) mitomycin C is a mitomycin C derivative, but not its masked compound. KW2083 differs from mitomycin C in various points. A phase I study of KW2083 by single intravenous injection was performed in 21 patients with advanced solid tumor. The dose limiting factor of this drug is marrow depression, and 70mg/m2 causing marked thrombocytopenia was determined as maximum tolerated dose. The thrombocyte count and the WBC count reached to nadir the minimum 2 to 3 weeks after and 1 to 2 weeks after the administration and recovered in 1 to 2 weeks and in 2 to 3 weeks respectively. As gastrointestinal symptoms, nausea or vomiting (38.1%), and anorexia (28.6%) occurred soon after the administration, and stomatitis and diarrhea were also observed in one case each. In addition, petechia, hemorrhagic tendency and fever were found in one case each. Patients receiving 70mg/m2 showed slight alopecia and transient slight in GOT and GPT elevation.

Animals↗
PubMed1983

Mitomycin-induced hemolytic-uremic syndrome. Successful treatment with corticosteroids and intense plasma exchange.

Mitomycin has been associated with microangiopathic hemolytic anemia and renal failure. We describe a patient with the adult hemolytic-uremic syndrome due to mitomycin who was successfully treated with intense plasma exchange therapy and corticosteroid therapy. Patients receiving mitomycin should have their conditions monitored closely for acute renal failure, thrombocytopenia, and hemolytic anemia.

Adenocarcinoma↗
PubMed1998

Outcomes of primary trabeculectomy with the use of adjunctive mitomycin.

OBJECTIVE: To investigate the efficacy and safety of adjunctive mitomycin when used during a primary trabeculectomy within a series of 89 consecutive patients at 1 and 2 years postoperatively. DESIGN: A cohort study of all patients who underwent primary trabeculectomy, performed by one of us (P.F.P.), between April 1, 1991, and December 31, 1994. Patients received topical mitomycin in conjunction with a corneal safety valve incision. A trabeculectomy was considered "successful" if it resulted in an intraocular pressure (IOP) of 21 mm Hg or lower and a 30% or greater reduction in the IOP at and after 1 year of follow-up, with or without medications and without a reoperation for an elevated IOP. Survival analysis was used to calculate success rates. RESULTS: The 1- and 2-year success rates were 85.4% and 77.9%, respectively. The mean IOP was reduced from 26.3 to 11.3 mm Hg at 1 year (n=68) and to 11.9 mm Hg at 2 years (n=56), with 60 (88.2%) of 68 patients off medication at 1 year and 47 (83.9%) of 56 patients off medication at 2 years. Trabeculectomy success rates were significantly lower in black compared with nonblack patients (76.2% vs 87.5% at 1 year, P=.03). Trabeculectomy failure occurred throughout the follow-up period. Endophthalmitis occurred in 2 (2.2%) of the patients, and hypotonia requiring revision occurred in 4 (4.5%) of the patients. CONCLUSIONS: Primary trabeculectomy with the use of intraoperative mitomycin lowered the IOP by 30% or more in 78% (at 2 years) to 86% (at 1 year) of the cases and is associated with a marked reduction in the percentage of patients who require glaucoma medication. Success rates must be evaluated in light of such risks as endophthalmitis and hypotony.

Administration, Topical↗
PubMed1994

Clinicopathologic features of excised mitomycin filtering blebs.

Using light and electron microscopy, we examined two conjunctival filtering blebs that had been treated with mitomycin just prior to trabeculectomy and were later excised due to ocular hypotony. Light microscopy showed attenuated epithelium, loosely arranged subepithelial connective tissue, and scattered acute and chronic inflammatory cells. Electron microscopy also showed these findings and demonstrated the presence of presumably viable activated fibrocytes in the subepithelial connective tissue. The presence of inflammatory cells in the blebs was attributed to concurrent infections and suggests that mitomycin does not completely suppress, but may attenuate, the inflammatory response. The mechanism of hypotony and bleb failure in the two eyes was most likely a combination of over-filtration and a persistent wound leak due to a lack of postoperative subconjunctival fibrosis secondary to treatment with mitomycin.

Adolescent↗
PubMed1995

Effect of mitomycin C and fluorouracil-supplemented trabeculectomies on the anterior segment.

OBJECTIVES: To determine whether there is increased risk to the corneal endothelium when mitomycin C is used in trabeculectomy surgery instead of fluorouracil, and whether these agents play a role in accelerating cataract formation. DESIGN, SETTINGS, AND PARTICIPANTS: We analyzed the corneal endothelium and the lens preoperatively and postoperatively in 30 eyes of 21 patients who underwent either a fluorouracil- or mitomycin C-supplemented trabeculectomy. RESULTS: No significant differences were found between these two groups in the rate of cataract progression, magnitude of endothelial cell loss, or appearance of endothelial cell morphologic characteristics. Endothelial cell loss accounted for approximately 7% to 8% of the preoperative counts in both groups. In addition, four (27%) of 15 eyes in each group showed evidence of cataract progression as graded by the Lens Opacities Classification System II. CONCLUSION: Fluorouracil- and mitomycin C-supplemented trabeculectomies cause similar changes in the lens and corneal endothelium.

Aged↗
PubMed1996

Endophthalmitis after filtering surgery with mitomycin.

OBJECTIVE: To identify the incidence, causative organisms, and clinical outcomes of eyes with bleb-associated endophthalmitis after glaucoma filtering procedures with adjunctive mitomycin. METHODS: Retrospective analysis of 773 consecutive eyes that underwent glaucoma filtering surgery at the Bascom Palmer Eye Institute, Miami, Fla. The course of 609 eyes from 485 patients with a minimum of 3 months of follow-up were reviewed. RESULTS: Mean follow-up was 16.0 +/- 11.5 months (range, 3-48 months). Of the 609 eyes, 13 (2.1%) developed bleb-associated endophthalmitis an average of 18.5 +/- 13.2 months after surgery (range, 1-45 months). The incidence of bleb-associated endophthalmitis was significantly greater after inferior trabeculectomy (7.8% per patient-year) than after superior trabeculectomy (1.3% per patient-year) by Kaplan-Meier estimates (P = .02, log rank test). The cumulative incidence was 13% for inferior limbal blebs and 1.6% for superior limbal blebs. Nine (69.2%) of the 13 eyes were culture positive. Streptococcus sanguis and Haemophilus influenzae (6/13 [46.2%]) were the most frequent causative organisms. The mean increase in intraocular pressure after endophthalmitis treatment was 1.2 mm Hg, with a mean decrease in visual acuity of 1.42 logMAR units. Eight (61.5%) of the 13 eyes had a final acuity of 20/400 or better. CONCLUSIONS: The incidence of bleb-associated endophthalmitis after guarded filtering surgery performed with adjunctive mitomycin is higher than the reported rate in eyes undergoing filtering surgery without the use of antifibrotic agents (0.2%-1.5%). Inferior limbal trabeculectomy carries the highest risk of infection. Eyes with mitomycin blebs maintained excellent filtration capacity. However, after treatment of the infection, the visual outcomes were generally poor.

Adolescent↗
PubMed1998

OK-432 and 5-fluorouracil, doxorubicin, and mitomycin C (FAM-P) versus FAM chemotherapy in patients with curatively resected gastric carcinoma: a randomized Phase III trial.

BACKGROUND: The streptococcal agent OK-432 is used widely as a potent biologic response modifier. Accumulated evidence suggests that OK-432 exerts antineoplastic effects by a direct cytotoxic or inhibitory effect on tumor cells. The clinical efficacy of OK-432 has been reported for various tumors. In this randomized Phase III study, the authors compared 5-fluorouracil (5-FU), doxorubicin, mitomycin C, and the intradermal administration of OK-432 (FAM-P) with the standard FAM regimen in patients with gastric carcinoma who underwent curative resection. METHODS: From May 1988 until November 1991, a total of 99 patients were entered into this randomized trial. The patients were stratified according to the American Joint Committee on Cancer stage of disease (i.e., Stage IB, II, and III). Fifty patients were treated with the FAM regimen here and throughout text.: 5-FU, 750 mg intravenously (i.v.), on Days 1, 8, 29, and 36; doxorubicin, 30 mg/m2 i.v., on Days 1 and 29; and mitomycin C, 10 mg/m2 i.v., on Day 1. Forty-nine patients received the FAM-P regimen: 5-FU, 750 mg i.v., on Days 1, 8, 29, and 36; doxorubicin, 30 mg/m2 i.v., on Days 1 and 29; mitomycin C, 10 mg/m2 i.v., on Day 1; and OK-432 5.0 Klinishe Einheit (clinical unit) injected intradermally weekly. RESULTS: The survival difference was statistically significant between the patients receiving the FAM and FAM-P regimens (5-year survival of 52% vs. 62%; P = 0.04). A comparison between disease free survival in FAM and FAM-P patients showed a borderline advantage for the FAM-P group (P = 0.053). When Stage IB, Stage II, and Stage III patients were analyzed separately, the difference in survival between two regimens was significant in Stage III patients (P = 0.049) and the disease free survival was of borderline significance (P = 0.06), but not in patients with Stage IB and II disease. The significant toxicity of OK-432 was mild fever, which was controlled with acetaminophen. CONCLUSIONS: The results of this study show that OK-432 may be an active, well tolerated agent for the treatment of curatively resected gastric carcinoma. However, these findings should be confirmed by a multicenter randomized study with a large sample size.

Adenocarcinoma↗
PubMed1981

The morphologic effects of mitomycin C in mammalian urinary bladder.

This investigation was intended to determine the morphologic changes of mitomycin C. It is part of a series of experiments designed to evaluate the cytologic and histologic effects of topical chemotherapeutic agents using the FANFT experimental model system in mice. The results for mitomycin C are very similar to those previously reported for thio-tepa. The indicate that these chemicals produce few, if any, drug-specific light microscopic alterations. Rather, mitomycin C and thio-tepa apparently act as toxic substances, causing increased exfoliation, degeneration, and necrosis of urothelial cells. The implications of these findings and suggestions for future investigations are discussed.

Administration, Topical↗