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PubMed1986

Mitomycin C-induced bidirectional transcription from the colicin E1 promoter region in plasmid ColE1.

Treatment of a colicinogenic culture with mitomycin C induces convergent transcription from two adjacent promoters at the beginning of the colicin E1 gene. S1-mapping and primer extension assays indicate that the mitomycin C-inducible transcripts correspond to colicin E1 mRNA (cea mRNA) and to a transcript, designated RNA-C, that may code for an entry exclusion function. Nucleotide sequences that strongly resemble a consensus sequence for LexA protein binding sites span the transcription start points for cea mRNA and RNA-C. These putative operator sequences overlap by one base pair and bind LexA protein (Ebina, Y., Takahara, Y., Kishi, F., Nakazawa, A. and Brent, R. (1983) J. Biol. Chem. 258, 13258-13261). The data suggest that mitomycin C-induced bidirectional transcription from the cea mRNA and RNA-C promoters is controlled by the SOS regulatory system of Escherichia coli.

Bacteriocin Plasmids↗
PubMedDate not supplied

Expression of the SOS response following simultaneous treatment with methyl-nitrosoguanidine and mitomycin C in Escherichia coli.

Simultaneous treatment of Escherichia coli cultures with methyl-nitrosoguanidine and mitomycin C induces recA-dependent inhibition of respiration but not inhibition of cell division. This pattern of SOS functions expression is the same as that is found following treatment with methyl-nitrosoguanidine alone and contrary to the pattern induced after mitomycin C addition. The same result is obtained when a culture of E. coli RecA441 (formerly tif) is shifted to 42 degrees C and treated simultaneously with methyl-nitrosoguanidine. The suppressor effect of this compound over the pattern of SOS functions expression induced by mitomycin C or high temperature in recA441 mutants is directly related to the increase in its dose. Moreover, the division temperature-sensitive mutant ftsA treated with methyl-nitrosoguanidine and high temperature does not show any decrease in its normal filamentous growth when cultured at 42 degrees C. This indicates that the effect of methyl-nitrosoguanidine on the recA-independent inhibition of cell division is not due to any indiscriminate effect of this compound over the division process. These results suggest that the specific kind of lesion caused in DNA is very important in determining which SOS function is induced.

Antibiotics, Antineoplastic↗
PubMed1991

In vitro activation of murine bone marrow-derived macrophages with cisplatin and mitomycin-C.

Peritoneal macrophages from BALB/c mice after treatment for 24 h in vitro with cisplatin, lipopolysaccharide (LPS) or mitomycin-C were rendered significantly cytotoxic against L-929 tumor target cells. In a similar experiment none of these agents could induce tumoricidal activity of fresh non-adherent bone marrow cells (NABMC). NABMC when incubated in medium alone or in medium containing L-929 culture medium (L-929 CM), a form of macrophage colony stimulating factor (M-CSF), for three days matured to macrophages which were positive for non-specific esterase staining. These bone marrow-derived macrophages cultured with medium alone did not respond to cisplatin. LPS or mitomycin-C for induction of tumoricidal activity whereas bone marrow derived macrophages with that were incubated with L-929 CM showed also significantly enhanced cytotoxicity after treatment with cisplatin, LPS and mitomycin-C. Culturing of NABMC with L-929 CM significantly enhanced cell survival as compared to the cells incubated in medium alone. These results suggest that bone marrow cells not only mature in L-929 CM but also are primed by L-929 CM for induction of tumoricidal activity.

Animals↗
PubMed1984

Adriamycin and mitomycin C as initial chemotherapy for advanced breast cancer.

Adriamycin and mitomycin C in combination have been tested in the treatment of advanced breast cancer. In an initial pilot study 11 heavily pretreated patients received mitomycin C alone and 2 (18%) achieved partial responses. Subsequently, 27 patients who had not received prior chemotherapy for advanced breast cancer were treated with adriamycin 40 mg/m2 + mitomycin C 10 mg/m2 i.v. every 3 weeks. Six (22%) achieved complete and 10 (37%) achieved partial responses, giving an objective regression frequency of 59%. The median duration of response was 37 weeks (range 8-55+ weeks).

Adult↗
PubMed1984

Phase II trial of mitomycin-C in patients with small cell carcinoma of the lung after failure on combination chemotherapy.

Mitomycin-C was evaluated in a disease-oriented phase II trial in patients with small cell lung cancer who had failed prior conventional chemotherapy. The drug was given as a direct i.v. injection of 15 mg/m2 repeated every 6 weeks. No objective tumor response was observed among 15 evaluable patients. This precludes a 20% level of activity with 95% confidence. Leukopenia (60% of patients) and thrombocytopenia (20% of patients) were common-effects observed. One patient developed a microangiopathic hemolytic anemia after a total mitomycin-C dose of 42 mg. We conclude that mitomycin-C in this dose and schedule is an inactive agent in previously treated patients with small cell lung cancer.

Adult↗
PubMed1995

Noncovalent binding of a mitomycin C metabolite, 2,7-diaminomitosene, to duplex DNA.

The major metabolite of mitomycin C, 2,7-diaminomitosene (DAM), interacts noncovalently with DNA. This was supported by ultraviolet-visible spectrum changes upon mixing with DNA and ethidium bromide displacement from DNA, measured as fluorescence changes. Moreover, DAM bound to DNA sufficiently strongly to hold DNA in a double stranded conformation under denaturing gel electrophoresis conditions commonly used to measure mitomycin C cross-links. These data show that generation of DAM and interaction with DNA represent a potential additional mechanism of DNA damage induced by mitomycin C.

Alkylation↗
PubMed1987

The search for more active and less toxic mitomycin and etoposide analogs.

Mitomycin C has broad-spectrum activity, but clinical utility is limited by cumulative myelosuppression. VP-16 also has broad-spectrum activity and, although myelosuppression is the dose-limiting toxicity, unlike mitomycin C it is predictable and reversible. Using toxicity reduction as a target for analog selection with mitomycin C has not yet resulted in a more clinically effective agent. Another goal would be to look for more rapid recovery and reversibility of myelosuppression, or compounds with greater antitumor activity or a different antitumor profile. With VP-16, analog evaluation is in an early stage, but selection based upon increased activity not reduced toxicity appears to be the avenue of choice and has resulted in the preliminary identification of analogs which in initial studies have superior activity to the parent compound.

Animals↗
PubMed1983

Response of a human colon adenocarcinoma (DLD-1) to X irradiation and mitomycin C in vivo.

Mice hosting a heterogeneous human colon xenograft tumor produced by subcutaneous injection of the DLD-1 tumor cell line were treated either with x irradiation alone, with mitomycin C alone (4 mg/kg), or with x irradiation given two hours after intraperitoneal injection of mitomycin C (4 mg/kg). Radiation alone produced a dose dependent delay in the time needed for tumors to regrow to twice their size at the time of irradiation, and in the mice receiving mitomycin C plus x irradiation, an additional growth delay equivalent to that produced by 3-3.5 Gy of X rays was seen at all X ray dose levels. As the DLD-1 tumor xenografts do not appear to possess a significant hypoxic fraction, we conclude that the two agents are acting in a simple additive cytotoxic manner by the killing of oxic tumor cells.

Adenocarcinoma↗
PubMed1996

Inducible synthesis of the mitomycin C resistance gene product (MCRA) from Streptomyces lavendulae.

The mcr locus from Streptomyces lavendulae confers high level resistance (> 100 micrograms/ml) to mitomycin C (MC) and related mitomycins when cloned into Streptomyces lividans. Production of the mcrA gene product (MCRA) was shown to be MC-inducible by identification of MCRA (M(r) of 54 kDa) using Western blot analysis and enzyme linked immunosorbent assay (ELISA). The magnitude of MCRA production was dependent on MC concentration, with primary induction starting at 0.1 microgram/ml and maximum induction at 10 micrograms/ml of the drug. Different levels of MCRA production were observed when other mitomycin metabolites were used as inducers, and the level of induction related directly to aziridine ring substitution on the individual molecules. Moreover, inducible synthesis of the mcr A gene product was unique to this structural class since production of MCRA did not occur as a general response to DNA damaging agents. The time profile of intracellular MCRA synthesis correlated with MC production in S. lavendulae, suggesting coordinated regulation of MC resistance and biosynthetic genes.

Antibiotics, Antineoplastic↗
PubMed1983

Modification of the sensitivity of CHO cells to mitomycin C by dibutyryl cyclic AMP.

The survival of CHO cells exposed to mitomycin C was decreased three times that of the cells treated with 1 mM dibutyryl cyclic AMP before mitomycin C treatment, as compared to the absence of treatment with this cyclic nucleotide. The sensitization effect began at 3-4 hours after the start of pre-treatment, reached a maximum at around 10 hours and continued to be effective. Post-treatment with the cyclic nucleotide for more than 12 hours increased the survival of CHO cells exposed to mitomycin C.

Animals↗
PubMed1991

In vitro study of the interaction of doxorubicin, thiotepa, and mitomycin-C, agents used for intravesical chemotherapy of superficial bladder cancer.

Several cytotoxic agents have been identified as effective in the treatment of superficial transitional cell carcinoma of the bladder, including doxorubicin, thiotepa and mitomycin-C. An in vitro study was conducted to assess the interactions of these three drugs against a well differentiated human bladder tumor cell line, RT-4, to identify and evaluate synergistic combinations among these agents. Cytotoxicity was evaluated by a colorimetric assay based on the capacity of viable cells to metabolize a tetrazolium dye, MTT, to produce a colored formazan product. The analyses of drug interactions were done by the isobolographic method (construction of isoeffect plots). The combination of doxorubicin and thiotepa was found to be the most synergistic, followed by the combination of doxorubicin and mitomycin-C. The combination of mitomycin C and thiotepa demonstrated an unpredictable effect. These findings suggest the combination of doxorubicin and thiotepa has potential advantage for chemotherapy of superficial bladder tumors.

Antineoplastic Agents↗
PubMed1987

Topical mitomycin C therapy for carcinoma of the bladder.

We studied 19 consecutive patients with biopsy proved carcinoma in situ of the bladder who had received 8 weekly doses of 30 mg. intravesical mitomycin C. Followup with cystoendoscopy, biopsy and cytology studies every 3 months ranged from 6 to 48 months, with an average of 21 months. A complete initial response was achieved in 15 patients, 11 of whom have remained free of tumor with no further therapy. The 4 patients who failed to respond to initial therapy subsequently were free of tumor after further intravesical mitomycin C (2), excision (1) or doxorubicin (1). Three patients died of unrelated diseases. Only 1 patient has had metastatic transitional cell carcinoma. No patient had undergone cystectomy or radiotherapy. These data indicate that mitomycin C achieves a high initial response in patients with carcinoma in situ of the bladder and maintains this control in many patients for months or years.

Administration, Intravesical↗
PubMed1984

Comparison of the efficacy of intravesical Bacillus Calmette-Guérin with thiotepa, mitomycin C, poly I:C/poly-L-lysine and cis platinum in murine bladder cancer.

The efficacy of intravesical Bacillus Calmette-Guérin for the treatment of the mouse bladder tumor MBT-2 was compared with that of thiotepa, mitomycin C, cis-diamminedichloroplatinum II and poly I:C/poly-L-lysine. MBT-2 cells were instilled into the bladder immediately after electrocauterization. Drug instillations were initiated 24 hours later and continued on a weekly basis for 4 weeks. Both Bacillus Calmette-Guérin and cis-diamminedichloroplatinum II significantly (p less than .0004) inhibited MBT-2 tumor implantation when compared to diluent-treated controls. Neither mitomycin C, thiotepa nor poly I:C/poly-L-lysine significantly inhibited tumor implantation. Mean tumor weights also were significantly (p less than .05) reduced in Bacillus Calmette-Guérin and cis-diamminedichloroplatinum II-treated mice, while tumor mean weights in mice treated with thiotepa, mitomycin C or poly I:C/poly-L-lysine were not significantly different than controls. These results suggest that the efficacy of intravesical Bacillus Calmette-Guérin in comparison with other drugs in the MBT-2 mouse bladder tumor model is similar to observations reported in human clinical trials in which intravesical Bacillus Calmette-Guérin was shown to be more effective than other cytotoxic drugs. These data further support the utility of the MBT-2 model for the study of the mechanisms by which Bacillus Calmette-Guérin inhibits bladder tumor growth.

Administration, Topical↗
PubMed1984

Absorption of doxorubicin-hydrochloride and mitomycin-C after instillation into noninfected and infected bladders of dogs.

The described investigations were carried out in order to determine the degree of absorption of doxorubicin, and mitomycin-C after intravesical instillation into noninfected or Staphylococcus aureus-infected bladders in beagle dogs. The drug concentrations in the bladder wall were determined using diffusion chambers with permeable membranes. Two hours after end of instillation of 10 mg. doxorubicin, a concentration of 1.4 ng. per ml. was measured in the bladder wall of noninfected animals, and 3.75 ng. per ml. in that of infected animals (p less than 0.05). The simultaneously measured serum concentration reached mean peak levels after 30 minutes. The concentrations in infected animals were 3 times higher (1.9 ng. per ml.) than in noninfected animals (0.6 ng. per ml.) (p less than 0.05). After instillation of 1 mg. per kg. bw. mitomycin-C the concentration in both groups of animals was below 0.06 micrograms per ml. Doxorubicin concentrations were determined with a radioimmunoassay and mitomycin-C with a micro-agar diffusion method.

Animals↗
PubMed1983

Severely contracted bladder following intravesical mitomycin C therapy.

Most superficial bladder tumors are best treated by transurethral resection. However, because of their multifocal origin and high rate of recurrence they often present challenging therapeutic problems. Intravesical chemotherapy often is used in such cases in the treatment and prevention of recurrent transitional cell carcinoma of the bladder. Recently, mitomycin C intravesical chemotherapy was shown to be effective in the treatment of superficial bladder tumors. No systemic toxicities were described but bladder irritation and drug-related palmar desquamation were noted. We report a case of a severely contracted bladder requiring urinary diversion following intravesical chemotherapy with mitomycin C. A possible relationship of this complication to the mitomycin C treatment is suggested.

Aged↗
PubMed1984

Sequence specificity of heat-labile sites in DNA induced by mitomycin C.

The sequence specificity of the mitomycin C-DNA interaction was directly determined by using DNA sequencing techniques and by using 3'- or 5'-end-labeled DNA fragments of defined sequence as substrates. Mitomycin C reduced with sodium borohydride induced heat-labile sites in DNA preferentially at specific sequences. The heat-labile sites were induced most preferentially at the dinucleotide sequence G-T ( especially Pu G-T), which was determined by scanning autoradiograms with a microdensitometer after gel electrophoresis. DNA was cleaved at the 3' side of deoxyguanosines and of some deoxyadenosines by heat treatment. Oligonucleotides produced by heat treatment after reaction with reduced mitomycin C contained phosphoryl groups at the 5' termini. The 3' termini seemed not to have simple structures, judging from their electrophoretic mobilities. Oxygen radicals such as singlet oxygen and hydroxyl radical were possibly involved in the induction of heat-labile sites.

Antibiotics, Antineoplastic↗
PubMed1991

Molecular mechanics simulations on covalent complexes of mitomycin C and its analogues with left-handed DNA duplexes.

We present molecular mechanics simulations on covalent complexes between d(GCGCGCGCGC).d(GCGCGCGCGC) in the left-handed double helical forms (B and Z) and potent antitumor antibiotics mitomycin C and three of its analogues using the all atom force field in the framework of the program AMBER(UCSF). The energy-refined models of the complexes show interesting networks of hydrogen-bonding interactions between the drugs and DNA groups in the minor groove of the left-handed helices. The energy-refined models suggest that mitomycins could bind strongly to left-handed helices. This result might be relevant to the interpretation of earlier experiments which suggested that DNA bound by mitomycin C underwent a transition to a non-Z left-handed structure.

Base Sequence↗
PubMed1987

Synthesis and antineoplastic activity of 1a-formyl and 1a-thioformyl derivatives of mitomycin C and 2-methylaziridine.

A select number of 1-formyl- and 1-thioformyl-2-methylaziridine derivatives and the corresponding 1a-substituted mitomycin C analogues were synthesized and tested for antineoplastic activity by using an in vivo test with murine P388 leukemia. Select compounds were also tested in vivo with murine melanoma B16. Several of the mitomycin C derivatives displayed activity and some of the mitomycin C analogues were comparable in activity to the parent compound.

Animals↗