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PubMed1990

A randomized study of two vindesine plus cisplatin-containing regimens with the addition of mitomycin C or ifosfamide in patients with advanced non-small cell lung cancer.

The current trial was carried out to assess the survival enhancement achieved, if any, by adding ifosfamide to vindesine and cisplatin (IVP) in contrast to mitomycin plus vindesine and cisplatin (MVP). Between June 1986 and September 1988, 110 patients were randomly allocated to receive either ifosfamide (3 g/m2 plus 3 g/m2 of mesna) or mitomycin 8 mg/m2, on days 1, 29, and 71 only. In both arms vindesine was given 3 mg/m2 weekly X 5 then every 2 weeks. In the MVP arm, 120 mg/m2 of cisplatin was administered on days 1 and 29 and then every 6 weeks, whereas in the IVP arm 100 mg/m2 of cisplatin was given on the same time schedule. One hundred three patients were evaluable for response and toxicity and 56% of patients had Mountain's Stage IV disease. The response rate was 26% (14/53 patients) in the MVP arm (95% confidence interval, 14%-39%) and 20% (ten of 50 patients) in the IVP arm (95% confidence interval, 10%-34%). Neither the response rate nor the median survival times were significantly different, although more nephrotoxicity was produced in the MVP arm, grade 1+ in 43% versus 26% in IVP arm (P = 0.04). Results obtained from this study fail to demonstrate that mitomycin or ifosfamide have a synergistic effect on the efficacy of the vindesine/cisplatin combination.

Adult↗
PubMed1990

Hepatic arterial embolization with microencapsulated mitomycin C for unresectable hepatocellular carcinoma in cirrhosis.

From 1986 to 1988, 35 patients with a hepatoma judged either inoperable or unresectable because of coexistent cirrhosis were treated with hepatic arterial embolization of mitomycin C microcapsules. Five of these 35 patients (14.5%) could not be treated because of inability to selectively cannulate the hepatic artery and were therefore excluded from the evaluation (feasibility rate, 86%). There were 24 men and six women with a median age of 57 years (range, 47 to 79) who could be classified as Okuda I (14 pts) or Okuda II (16 pts) and Child Class A:18 and Child Class B:12 in the remaining patients. A median dose of 0.5 mg mitomycin C/kg was administered to each subject and the treatment was repeated at 5 to 6 week intervals. Seventy courses were administered to these 30 patients (median, two courses/patient; range, 1 to 4). Minor complications were frequent (63%) but always either resolved spontaneously or after appropriate medical treatment. Neither severe renal nor hepatic toxicity was observed. No specific treatment related mortality was observed. When alpha-fetoprotein levels and tumor volume were assessed to evaluate the response to treatment using established criteria for identifying a response, an objective response was found in 43% of the cases treated. The actuarial median survival was 7 months and the 1-year actuarial survival was 36% (51% for those rated as Child Class A and 0% for those identified as Child Class B, P = 0.04 and 78% rated as Okuda Types I and 0% Okuda type II, P = 0.0001). The excellent quality of life and the increased survival rate experienced after mitomycin C microcapsule embolization suggest that this treatment modality can be used successfully in patients seen in the West who have unresectable hepatoma.

Aged↗
PubMed1984

Cell cycle perturbations in heterotransplanted squamous-cell carcinoma of the head and neck after mitomycin C and cisplatin treatment.

Cell kinetic studies are of interest for clarifying the concepts of chemotherapeutic strategy in the multimodality therapy of advanced squamous-cell carcinoma of the head and neck. A poorly-differentiated squamous-cell carcinoma of the head and neck heterotransplanted to nude mice was used for analyses of chemotherapeutically induced cell cycle perturbations. The heterotransplanted tumour, in its 15th or later passages in nude mice, was treated with either Mitomycin C or cisplatin. After determination of dose-response relationships and toxicity, treated tumours were biopsied at different times and cell cycle distribution pattern, 3HTdR incorporation into DNA, histology and tumour volume were recorded. Mitomycin C and cisplatin gave the same pattern of cell cycle perturbations, although the changes induced by cisplatin were more profound. There was an initial increase of the fraction of cells in the S phase, concomitant with a reduction of the fraction of cells in G0 + G1 phase. When these perturbations were normalized a transient increase of the fraction of cells in G2 + M phase was observed. However, while cisplatin caused an initial transient depression of DNA synthesis, the Mitomycin-C-treated tumours exhibited a short-lasting increase of DNA-synthesis. The maxima of the induced changes in cell cycle phase distribution and DNA-synthesis lasted for only 24-48 h, which may be of importance for scheduling combinations of drugs. Though both drugs induced profound changes in tumour volume growth and cell kinetics, there was no change in the histopathological picture of the treated tumours. Routine histopathological examination is thus not likely to be of value evaluating the effect of chemotherapy.

Animals↗
PubMed1990

New sugar mitomycin C analogues: preparation, murine P388 antitumor activity, and leukopenia induction.

Four new sugar:mitomycin C derivatives were synthesized by coupling of N-1 of mitomycin C with tetra-O-acetylglucopyranosyl isothiocyanate and 3,4,6-tri-O-acetyl-2-(N-acetylamino)-2-deoxyglucopyranosyl isothiocyanate. Conversion of each derivative to its water-soluble analogue was achieved by deacetylation, using saturated NH3:CH3OH. Antitumor activity, assessed using the in vivo murine P388 ascitic leukemia system, demonstrated efficacy comparable with the parent mitomycin C. However, unlike the highly myelosuppressive parent drug, optimal antitumor activity is achieved at doses which produce only limited leukopenia.

Animals↗
PubMed1986

Effect of mitomycin C on the neural tube defects of the curly-tail mouse.

Around 60% of the mouse mutants called curly-tail, have tail aberrations in the form of a coil or a kink, with or without lumbosacral spina bifida, and rarely, exencephaly. These neural tube defects (NTD) are the result of an incompletely penetrant recessive gene. A single injection of various doses (1-6 mg/kg) of the DNA inhibitor mitomycin C was given to pregnant curly-tail mice on day 7, 8, or 9 of gestation, and its effect on the NTD of the embryos was noted. No dose used was lethal to the embryo. When given on day 7 or day 8, mitomycin C markedly increased the number of exencephalics, and additionally, on day 8, it reduced the number of posterior abnormalities. However, on day 9, no exencephaly was produced, and there was a drastic reduction in the number of tail and spinal defects, the overall incidence of NTD being as low as 15% with 2 mg/kg. A twofold effect of mitomycin C on the curly-tail embryos was thus observed--according to the time in development it was administered, firstly, a teratogenic effect, and later, a "remedial" or preventive effect.

Animals↗
PubMed1998

1a-docosahexaenoyl mitomycin C: a novel inhibitor of protein tyrosine kinase.

A series of derivatives of mitomycin C conjugated with various fatty acids at position 1a was synthesized and the effect of these compounds on protein kinase activities was evaluated. 1a-Docosahexaenoyl mitomycin C (DMMC) selectively inhibited protein tyrosine kinase (PTK) activity in the postnuclear fraction of v-src-transformed NIH 3T3 cells although neither derivatives conjugated with other fatty acids or docosahexaenoic acid or mitomycin C did not. DMMC inhibited the activity of calmodulin-dependent kinase III and protein kinase A very weakly, and only barely affected protein kinase C activity. DMMC also attenuated autophosphorylation of immunoprecipitated p60v-src irreversibly. The addition of thiol compounds to the reaction mixture reversed the inhibition by DMMC, suggesting that some thiol moiety of PTK protein might be involved. DMMC also inhibited kinase activity of p210bcr-abl immunoprecipitated from the lysate of K562 cells. These results indicate that DMMC is a novel inhibitor of PTK.

3T3 Cells↗
PubMed1990

Antitumor activity and toxicity in animals of N-7[2-(4-nitrophenyldithio) ethyl] mitomycin C (BMY-25067).

BMY-25067, N-7[2-(4-nitrophenyldithio)-ethyl] mitomycin C was selected from a number of disulfide derivatives of the highly active compound RR150, N-7(thioethyl) mitomycin C for further study. BMY-25067 had tumor inhibitory effects equivalent to mitomycin C (MMC) against ascitic P388 and L1210 leukemias and M109 lung carcinoma in mice with i.p. treatment. However, it demonstrated superior activity against B16 melanoma with a high percentage of cures when both tumors and drug were given i.p. Additionally, in separate tests against B16 melanoma implanted s.c. with treatment i.v., BMY-25067 was also consistently superior to MMC. This activity was observed when therapy was initiated either one day post-tumor implant or delayed until the ninth day post-tumor implant. Slight activity was seen against a line of L1210 partially resistant to MMC and none against a line of P388 completely resistant to MMC. Against s.c. M109, BMY-25067 inhibited tumor growth but did not prolong survival with the treatment schedule used. At their respective maximum non-lethal doses in mice, BMY-25067 was less neutropenic than MMC. This was confirmed in ferrets which were also examined for the compound's effects on platelets. BMY-25067 appeared to have much less effect on platelets than MMC; the nadir for BMY-25067 was 3.8 x 10(5) platelets/cmm compared to 7 x 10(4) platelets/cmm for MMC when the drugs were compared at a dose ratio of 2:1, BMY-25067:MMC (determined to represent their relative potencies). This initial evidence of superior antitumor effectiveness particularly to a solid tumor separated from site of treatment and reduced hematologic toxicity suggest that BMY-25067 may be a worthwhile candidate for clinical trial.

Animals↗
PubMed1985

Synergistic anti-suppressor effect of mini cells prepared from Salmonella typhimurium and mitomycin C in EL 4-bearing mice.

The subcutaneous growth of EL4 cells was significantly accelerated when they were injected together with spleen cells collected from mice which had received EL4 cells SC 14 days previously, and all mice died within 18 days after receiving this mixture; 80% of mice which received a mixture of EL4 and spleen cells collected immediately after EL4 graft survived over 40 days. Spleen cells collected 14 days after EL4 graft suppressed the blastogenic responses of normal spleen lymphocytes to concanavalin A, pokeweed mitogen, and lipopolysaccharide of Escherichia coli in a mixed culture system. Acceleration of tumor growth was retarded when EL4 cells were injected together with spleen cells from EL4-bearing mice treated with both Salmonella typhimurium mini-cells and mitomycin C, and 60% of mice survived over 40 days. Blastogenic responses of normal spleen lymphocytes mixed with spleen cells from EL4-bearing mice treated with both mini-cells and mitomycin C were restored almost to control levels. The results suggest that combination treatment with mini-cells and mitomycin C synergistically inhibits the induction of suppressor cells in EL4-bearing mice.

Animals↗
PubMed1989

High-dose mitomycin C: activity in hepatocellular carcinoma.

Hepatocellular carcinoma is the most common cause of cancer death in Thai males. It is usually found to be inoperable, and the reported median survival for Thai patients is only 4.3 months. From October 1984 to December 1986, 30 cases of nonresectable hepatocellular carcinoma were treated at the National Cancer Institute, Bangkok, Thailand, with high-dose mitomycin C. Patients were given 20-25 m/m2 (median, 40 mg) by i.v. injection, followed by 10-12.5 mg/m2 (median, 20 mg) at 6-week intervals in responding patients until the disease progressed or toxicity was detected. In all, 23 patients were evaluable by WHO criteria. A partial response was achieved in 11 of 23 cases (48%); the median duration of this response was 7 months (range, 3-11 months). The median cumulative dose of mitomycin C was 80 mg (range, 40-120 mg). Toxicity was relatively well tolerated; only one patient developed an unusual erythematous, reticular skin rash that spontaneously disappeared within 1 month of injection of the drug. The median survival of responders was 12 months, and the longest survival was 18+ months. We conclude that high-dose mitomycin C given according to the present dose and schedule has antitumor activity in hepatocellular carcinoma in Thai patients. Although its response rate is as high as that produced by doxorubicin, with less toxicity, no complete response was achieved in this study.

Adult↗
PubMed1990

High-dose cisplatin and mitomycin C in advanced non-small cell lung cancer: a phase II study of the Northern California Oncology Group.

To investigate chemotherapeutic dose intensity in advanced non-small-cell lung cancer (NSCLC), we evaluated a pharmacokinetically designed schedule of high-dose cisplatin (200 mg/m2 per 28-day cycle) plus mitomycin C. Between March 1987 and March 1989, 62 patients were registered for a phase II study of the Northern California Oncology Group (NCOG). The treatment schedule consisted of cisplatin in hypertonic saline given on a divided days 1 and 8 schedule (100 mg/m2 on each day) plus mitomycin C given at a dose of 8 mg/m2 on day 1 of each cycle. In 61 patients evaluable for response analysis, the overall response rate was 39% (24/61), with a complete response being achieved in 6% (4/61) of cases and a partial response, in 33% (20/61). The response according to reviewed histologic subtype included squamous, 53% of patients (10/19); large cell, 31% (4/13); and adenocarcinoma, 34% (10/29). The median survival for all patients was 29.3 weeks. The mean cisplatin and mitomycin C delivered dose intensities in this study were 45 mg/m2 per week (90% of the projected dose) and 1.5 mg/m2 per week (75%). The toxicity of this combination regimen in the 62 enrolled patients was significant but manageable. Leukopenia (WBC, less than 1,000/mm3) and thrombocytopenia (platelets, less than 25,000/mm3) occurred in 3% and 8% of patients treated, respectively. Dose-limiting renal toxicity and clinically significant ototoxicity developed in 8 patients each (13%), and a peripheral sensory neuropathy was observed in 17 cases (27%). Whether this type of dose-intensive therapy results in an improved therapeutic index in NSCLC is currently being evaluated in a randomized comparative trial versus standard-dose cisplatin therapy.

Adult↗
PubMed1987

Sensitivity of mitomycin-C treated McCoy cells for isolation of Chlamydia trachomatis from genital specimens.

A new cell culture method was developed for the diagnostic isolation of Chlamydia trachomatis using McCoy cells pretreated with mitomycin-C. This drug acts on the cell by producing cross links between strands of DNA and results in the production of large, flat cells, which are similar to irradiated cells, and large chlamydial inclusions. In tests using a laboratory isolate of Chlamydia trachomatis, there were significantly more inclusions produced in mitomycin-treated monolayers than in cycloheximide-treated monolayers. Using clinical specimens, significantly more isolates were obtained in mitomycin-treated cells than in cycloheximide-treated cells. The new cell culture technique therefore offers a cell culture method which has the advantages of producing large inclusions similar to irradiated cells but with the convenience of drug treatment.

Cell Line↗
PubMed1991

The influence of stromal cells on the MTT assay (I)--In vitro chemosensitivity of the tumor and stromal cells to mitomycin C.

To clarify the influence of stromal cells on the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide assay (MTT assay), a gastric carcinoma cell line (KATO-III) and a human fibroblast cell line (IMR-90) were subjected to a colorimetric assay, in which the chemosensitivity KATO-III was found to be highly sensitive to mitomycin C at 10 micrograms/ml, whereas IMR-90 was insensitive to mitomycin C at the same concentration. When the mixtures of these two cell lines were tested by the assay, a mixture of more than 25 per cent stromal cells reduced the sensitivity of KATO-III to mitomycin C. This suggested that the stromal cells in fresh surgical specimens might reduce the apparent sensitivity of the tumor cells.

Drug Screening Assays, Antitumor↗
PubMed1989

Loss of penicillin resistance in Paracoccus denitrificans induced by mitomycin C and acridine orange.

In an attempt to eliminate the penicillin resistance gene of P. dentrificans by curing agents, such as acridine orange (AO) and mitomycin C, it was observed that AO treatment caused temporary phenotypic curing where development of sensitivity was a function of concentration of both the curing agent and benzylpenicillin. However, curing with mitomycin produced sensitive clones at a frequency of 6 X 10(-3) and two permanently cured clones were isolated. Heavy metal resistance and resistance to other drugs, however, remain unchanged in the mitomycin-cured isolate.

Acridine Orange↗
PubMed1990

Mitomycin C and mitoxantrone chemotherapy for advanced breast cancer: efficacy with minimal gastrointestinal toxicity and alopecia.

In an attempt to examine the possibility of decreased toxicity in patients with advanced breast cancer who had not previously received chemotherapy, 33 women were given combination chemotherapy consisting of mitomycin C (10 mg/m2) every 6 weeks and mitoxantrone (6 mg/m2) every 3 weeks. The patients had predominantly visceral disease and received a median of two cycles of therapy. Of the 32 evaluable subjects, 15 (47%) achieved a partial response lasting a median of 7 months. Hematological toxicity was generally mild, although there were two episodes of sepsis. One patient developed hemolytic-uremic syndrome, and one subject developed pulmonary fibrosis, both presumably attributable to treatment with mitomycin C. Another patient died of hepatic failure (hepar lobatum). Thus, there were five patients who sustained life-threatening toxicities; this may have been due to the poor performance status and advanced age of some of the patients. Gastrointestinal toxicity and alopecia were minimal. Patient acceptance was high and there was an improvement in symptomatology in the majority of patients. In conclusion, mitomycin C and mitoxantrone chemotherapy is an active drug combination for the treatment of advanced breast cancer that seldom causes significant distressing gastrointestinal side effects or alopecia; however, the duration of response to this regimen appears to be shorter than that obtained with either cyclophosphamide - methotrexate - 5-fluorouracil (CMF) or cyclophosphamide - Adriamycin - 5-fluorouracil (CAF) combination chemotherapy.

Alkylating Agents↗
PubMed1989

DNA sequence-specific adducts of adriamycin and mitomycin C.

Adriamycin and mitomycin C were reduced by xanthine oxidase/NADH in the presence of a DNA template comprising a stable initiated ternary transcription complex derived from the lac UV5 promoter. Subsequent elongation of the transcription complex treated with mitomycin C revealed high levels of terminated transcripts one nucleotide prior to G residues on the coding strand (i.e. at X of XpC sequences of the non-coding strand). Lower levels of termination occurred with adriamycin, and these were also one nucleotide prior to G residues of the coding strand, but with greater sequence specificity since they were observed mainly at G of GpC sequences of the non-coding strand. The same sites were also observed with adriamycin in the absence of reducing conditions and the level of termination at these sites was enhanced up to 10-fold by Fe2+ and Fe3+, but not by Cu2+, Zn2+, Co2+ or Ni2+. These results suggest that an iron-adriamycin complex with DNA is highly sequence-specific and results in adducts, similar to those of mitomycin C, which can terminate the transcription process. Such a mechanism offers new insights into the possible mode of action of anthracyclines.

Base Sequence↗
PubMed1989

Use of the cytokinesis-block method for the analysis of micronuclei in V79 Chinese hamster lung cells: results with mitomycin C and cyclophosphamide.

The cytochalasin B (CYB)-blocked binucleated cell assay has been explored to analyze micronuclei and cell cycle kinetics using 2 known mutagenic carcinogens in V79 Chinese hamster lung cells. To determine the optimum time to obtain the maximum number of binucleated cells for micronucleus analysis, duplicate cultures of exponentially growing cells were treated with 3 micrograms/ml CYB for varying durations (8-48 h). A peak appearance of binucleated cells at 16 h in the presence of CYB suggested this as an optimum time for micronucleus analysis in binucleated V79 cells. To evaluate the capacity for induction of micronuclei in V79 cells, 2 mutagenic carcinogens, mitomycin C (0.125-1.0 micrograms/ml) and cyclophosphamide (2-12 micrograms/ml) were tested in duplicate cultures. Mitomycin C, a direct-acting alkylating agent, caused approximately an 18-fold increase in micronucleus frequency over controls at the highest concentration tested (1.0 micrograms/ml), and this increase occurred in a dose-related manner (r = 0.92). The concentrations of mitomycin C tested also caused a significant dose-related cell cycle delay, thus suggesting cytotoxicity to V79 cells. Cyclophosphamide, an indirect-acting alkylating agent, requiring the presence of S9 mix, caused approximately a 17-fold increase in micronucleus frequency over controls at the highest tested concentration (12 micrograms/ml), with a clear dose response (r = 0.99). The various concentrations of cyclophosphamide also caused cytotoxicity in a dose-related fashion. Thus, this study demonstrates the usefulness of the cytokinesis-block method in V79 cells as a possible screen to analyze micronucleus induction and cytotoxicity. Because this approach is much less labor intensive than conducting a structural chromosomal analysis, this assay has great potential both as an initial screen for clastogenic activity and as a tool for investigating the underlying mechanisms for clastogenicity.

Animals↗
PubMed1982

Reactivity of mitomycin C with synthetic polyribonucleotides containing guanine or guanine analogs.

The guanine residues in nucleic acids are believed to be the major covalent binding site of the antibiotic mitomycin C. To identify the specific functional group in guanine which reacts with mitomycin C, reactions were run between the antibiotic and poly(G) analogs in which guanine was blocked at the N-7 or O-6 position, or lacked the 2-amino group. Binding ratios were affected to a small extent in the two former cases, but binding was significantly decreased in the absence of the 2-amino group. These results indicate that the most likely binding site of mitomycin C in synthetic polyribonucleotides is the 2-amino group of guanine residues.

Antibiotics, Antineoplastic↗
PubMed1982

Defective repair of mitomycin C crosslinks in Fanconi's anemia and loss in confluent normal human and xeroderma pigmentosum cells.

Crosslink repair of mitomycin C-induced interstrand crosslinks was studied in exponentially growing and confluent normal human, transformed W138CT-1, Fanconi's anemia (FA) and xeroderma pigmentosum (XP) group-A fibroblasts by the assay methods of alkaline sucrose centrifugation, hydroxyapatite column chromatography and S1-nuclease digestion. These three methods demonstrated unequivocally that crosslinking occurred at a rate of 0.13 crosslinks/10(8) Da per microgram per ml mitomycin C (less than or equal to 10 micrograms/ml) and the first half-excision of crosslinks followed the rapid first-order kinetics of 2-3 h half-life in exponentially-growing normal, WI38CT-1 and XP group-A cells. However, the first half-excision was completely defective in three out of the four FA strains tested and severely retarded in an FA strain. These results strongly support our previous observations in different strains of normal human, FA and XP group-A cells. An important new addition is that confluent, otherwise proficient, normal and XP cells almost completely lost the ability of the first, rapid half-excision of mitomycin C crosslinks in their DNA. This probably suggests that the enzyme or regulatory factor responsible for the half-excision, which differs from that for nucleotide excision repair, present constitutively in confluent cells, may be induced or activated only in the cycling cells. However, its relation to a defective FA factor is not clear at present.

Anemia, Aplastic↗