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PubMed1996

Interferons modify in vitro proliferation of human bladder transitional cell carcinoma in the presence of doxorubicin and mitomycin C.

PURPOSE: The aim of the present study was to investigate whether interferons with their known antitumor activity modify the response of human bladder carcinoma cells to antitumor drugs. MATERIALS AND METHODS: We investigated the in vitro effect of doxorubicin, mitomycin C and the interferons alpha and gamma on cell proliferation in human bladder carcinoma cell lines as measured by 5-bromo-2'-deoxy-uridine (BrdU) incorporation. RESULTS: Exposure of RT 112 (but not EJ 28) cells for 2 hours to doxorubicin (500 ng./ml.) and mitomycin C (200 ng./ml.) reduced the proliferation rate to 85.9 +/- 3.3% (n = 4) and 89.3 +/- 4.0% (n = 4) of control. Treatment for 2 days with interferon alpha and gamma up to the highest concentration (200 U/ml.) showed no effect. The combination of 100 U/ml. interferon alpha and doxorubicin decreased proliferation significantly. At 50 ng./ml. the proliferation rate was decreased to 88.0 +/- 5.7% of control and at 500 ng./ml. to 67.7 +/- 3.1%. Thus interferon alpha seems to increase the sensitivity of the cells to doxorubicin. Cells treated with 20 ng./ml. mitomycin C after pretreatment with interferon alpha showed a dramatic decrease in cell proliferation (from 98.8 +/- 2.1% to 80.2 +/- 4.0% of control). This decrease was similar in the presence of 200 ng./ml. mitomycin C. Thus mitomycin C seems to render cells more sensitive to the antiproliferative action of interferon alpha. Interferon gamma had only minor effects on the response of the cells to doxorubicin or mitomycin C. CONCLUSIONS: These studies suggest that exposure to interferon alpha increases the efficacy of anticancer drugs in vitro, probably by several mechanisms. Potential consequences of this finding for the therapeutic regime employed for treatment of bladder carcinoma are discussed.

Antineoplastic Agents↗
PubMed1997

Mitomycin-C in laser sclerostomy: benefit and complications.

BACKGROUND AND OBJECTIVE: The authors studied the effect of topical mitomycin-C administration on the maintenance of filter function and intraocular pressure (IOP) following laser sclerostomy. PATIENTS AND METHODS: Twenty-six patients with a presumed high risk of episcleral scarring were treated intraoperatively with topical mitomycin-C (0.5 mg/ml) for 3 to 5 minutes. Their IOPs were monitored for at least 2 years. The IOP data of these patients were compared with the results for 46 patients who underwent the identical procedure without antimetabolite. RESULTS: IOPs below 23 mm Hg were achieved in 70% of the mitomycin-C-treated patients. Compared with the non-mitomycin-C group, the rate and duration of early postoperative hypotony was significantly increased in the mitomycin-C-treated group. CONCLUSION: Mitomycin-C is useful for maintaining successful filter function in patients with unfavorable prognoses. However, severe and persistent hypotony may occur.

Administration, Topical↗
PubMed1997

[Does the dosage of mitomycin-C applied during filtering surgery of glaucoma vary with the individual surgeon?].

PURPOSE: The purpose of this study was to estimate the quantity of mitomycin-C contained in sponges prepared by different surgeons as compared to that in applicators of the type used in Schirmer's test graduation (5 x 5 mm). MATERIALS AND METHODS: Four surgeons each cut and prepared 10 sponges for intraoperative use according to their usual method. The same procedure was performed with 10 Schirmer's test graduations. Each sponge and each graduation was immersed in a solution of mitomycin-C 0.2 mg/ml, and the quantity of antibiotic (microgram) in each was calculated as the difference between wet and dry weight. RESULTS: The mean quantity (+/-SEM) of mitomycin-C contained in cut sponges was 9.6 +/- 4.4 micrograms (range 1.9-17.3), and differences between surgeons were statistically significant (p < 0.0001). The mean quantity of antibiotic in Schirmer's test graduation was 1.7 +/- 0.3 micrograms (range 1.1-2.5), and the differences between surgeons were not statistically significant (p = 0.79). CONCLUSION: The quantities of mitomycin-C contained in sponges prepared for glaucoma surgery differed for a given surgeon and between surgeons. Thus, variations in the doses applied to the sclera could account for certain complications due to mitomycin-C. The use of a Schirmer's test graduation improves predictability for the quantity of mitomycin-C applied to the sclera.

Antimetabolites↗
PubMed1996

Intraoperative and postoperative use of mitomycin-C in the treatment of primary pterygium.

BACKGROUND AND OBJECTIVE: The effectiveness of 0.04% mitomycin-C, either postoperatively for 2 weeks or intraoperatively as a single dose, as an adjunct in the surgical treatment of primary pterygium was evaluated. PATIENTS AND METHODS: Mitomycin-C was used in addition to the bare sclera technique in 43 eyes with pterygia. The mean follow-up time was 18.5 months for the 24 eyes in the postoperative mitomycin-C group, 10.3 months for the 19 eyes in the intraoperative mitomycin-C group, and 17.3 months for the 17 eyes in the control group (eyes that had undergone surgical excision only). RESULTS: The recurrence rate was 4.2% with postoperative administration, 5.3% with intraoperative application, and 41.2% in the control group. There was a significant reduction in recurrence rates for both the postoperative and the intraoperative mitomycin-C groups compared with the control group (P = .005 and P = .01, respectively). However, recurrence rates were not statistically different according to the type of application. No serious side effect occurred during the follow-up period. CONCLUSION: Topical mitomycin-C, either intraoperatively or postoperatively, as an adjunct decreases the recurrence rate of primary pterygium. Intraoperative application seems advantageous because it decreases the symptomatic side effects and restricts the inappropriate use by the patient.

Administration, Topical↗
PubMed1998

Half corneal light shield as a delivery system for standardized application of mitomycin C.

PURPOSE: The authors develop a simple and economical method of applying reproducible intraoperative doses of mitomycin C for glaucoma filtering surgery. METHODS: A three-part protocol was developed to study several properties of half corneal light shields (HCLSs). Part A tested the amount of mitomycin C (0.4 mg/ml) absorbed, the expansion dimensions attained, and the amount released to filter paper. In part B, the in vitro release of mitomycin C to an enucleated pig eye was examined. In part C, the in vivo release during intraoperative filtering surgery was tested. RESULTS: The amount of mitomycin C solution absorbed by the HCLSs ranged from 1.07 x 10(-2) mg to 1.19 x 10(-2) mg; expansion width ranged from 6.8 mm to 7.0 mm; expansion height ranged from 3.6 mm to 3.8 mm; expansion thickness was constant at 0.6 mm. The amount of solution released to filter paper ranged from 6.8 x 10(-3) mg to 8.6 x 10(-3) mg. The amount of solution transferred to the pig eye ranged from 1.0 x 10(-3) mg to 2.7 x 10(-3) mg. The amount of solution released in filtering surgery ranged from 2.0 x 10(-3) mg to 4.8 x 10(-3) mg. CONCLUSIONS: The contact surface area, the amount absorbed, and the amount released by each HCLS was reproducible. The uniform thickness theoretically provides a uniform distribution of mitomycin C. This method may allow standardization of intraoperative mitomycin C application, and may reduce the incidence of complications.

Absorption↗
PubMed1998

Results of trabeculectomy with 0.3 mg/ml mitomycin C titrating exposure times based on risk factors for failure.

PURPOSE: To examine the efficacy of trabeculectomy with mitomycin C 0.3 mg/ml using titrated exposure times. METHODS: A retrospective chart review of consecutive patients undergoing trabeculectomy in an academic referral glaucoma clinic was performed. All patients received trabeculectomies performed by one surgeon (M.B.S.). The study included 57 eyes of 57 patients using mitomycin C with exposure times titrated from one to five minutes based on risk factors for trabeculectomy failure. Surgical success was defined as a final intraocular pressure (IOP) of less than 21 mmHg with or without medications or a 25% reduction in IOP if preoperative IOP was 21 mmHg or less. Patients requiring repeat trabeculectomies were considered failures regardless of their final IOP. Patients receiving different mitomycin C exposure times were compared but statistical analysis was not used because these subgroups were not randomized. RESULTS: An overall surgical success rate of 84.2% was achieved at a mean follow-up of 11.9 months. The surgical success rate and percentage IOP reduction was similar between exposure time subgroups. Hypotonous maculopathy observed in three patients (5.3%). All cases of hypotonous maculopathy was occurred in the lower-risk patients receiving one to three minute exposure times to mitomycin C. CONCLUSIONS: We believe mitomycin C should be used sparingly if at all in patients at lower risk for trabeculectomy failure. This concentration of mitomycin C with four to five minute exposure times appears to be efficacious for patients with multiple risk factors for trabeculectomy failure.

Administration, Topical↗
PubMed1964

INFLUENCE OF BIOLOGICAL METHYLATION ON THE BIOSYNTHESIS OF MITOMYCIN A.

Kirsch, E. J. (Lederle Laboratories, Pearl River, N.Y.), and J. D. Korshalla. Influence of biological methylation on the biosynthesis of mitomycin A. J. Bacteriol. 87:247-255. 1964.-Methionine-methyl-C(14) was shown to contribute radioactive carbon to the mitomycin antibiotic complex synthesized by Streptomyces verticillatus in a simple synthetic medium containing glucose and inorganic salts. The position of radioactivity in mitomycin A was determined by selective hydrolysis of the 7 and 9a methoxyl functions. Essentially all of the radioactivity incorporated was distributed evenly between these two substituent groups. Mitomycin A, synthesized by washed resting cells of S. verticillatus at the expense of internal metabolites, also incorporated methyl label. When the methionine antagonist, d,l-ethionine, was added to resting cells at a concentration causing 65% inhibition of antibiotic synthesis, incorporation of radioactive methyl groups was reduced to the same extent. Synthetic medium supplemented with d,l-ethionine supported about 90% maximal growth of the culture, but antibiotic biosynthesis was markedly inhibited. The addition of the inhibitor during the period of rapid antibiotic synthesis resulted in cessation of further increases in antibiotic titer. l-Methionine was shown to be capable of reversing ethionine inhibition; the extent of reversal was dependent on the concentration, as well as on the time of addition of amino acid. The data suggest the critical nature of a methyl transfer system in the biogenesis of biologically active mitomycins.

Amino Acids↗
PubMed1986

Degradation kinetics and mechanism of N6-[(dimethylamino)methylene]mitomycin C in aqueous solutions.

The degradation of N6-[(dimethylamino)methylene]mitomycin C, a semisynthetic analogue of mitomycin C, was studied in aqueous solution. The compound degraded rapidly and followed pseudo-first-order kinetics in both acidic (pH less than 5) and basic pH greater than or equal to 9) media. In the near-neutral pH region, however, biphasic kinetics were observed. At the pH of maximum stability (6.5), 10% activity was lost after approximately 6 h at 22 degrees C. Citrate and phosphate species were catalytic at pH 6.5. Spectrophotometric and HPLC methods were used to elucidate the degradation mechanism at pH 7-9. Under these conditions, equilibrium addition of one water molecule into the amidine side chain occurred, followed by parallel formation of mitomycin C and N6-(formyl)mitomycin C. The latter compound subsequently hydrolyzed to mitomycin C.

Buffers↗
PubMed1982

Pharmacokinetics of mitomycin C in rabbit and human.

A sensitive and specific high-pressure liquid chromatographic assay was developed to characterize the plasma elimination and urinary excretion of mitomycin C in humans. Extraction of mitomycin C and an internal standard, porfiromycin, from plasma by chromatography over a non-ionic resin, Porapak Q, yields high recovery of both compounds and facilitates measurement of as little as 5 ng mitomycin C by reversed-phase high-pressure liquid chromatography. The assay was used to characterize the plasma elimination of mitomycin C in rabbits and was shown to be applicable to the characterization of the pharmacokinetics of mitomycin C in humans receiving as little as 8 mg/m2.

Animals↗
PubMed1988

Teratogenic interactions between methylmercury and mitomycin-C in mice.

Pregnant mice were given p.o. various nonteratogenic doses (0, 2.5, 5 and 10 mg/kg) of methylmercuric chloride on day 9 of pregnancy, and then injected i.p. with a teratogenic dose (4 mg/kg) of mitomycin-C on day 10. Major malformations produced by mitomycin-C alone were cervical rib and vertebral anomaly, polydactyly of the hindlimb and tail anomaly. Combined treatment significantly increased the incidence of these malformations, showing the dose-effect relationship of methylmercury, whereas methylmercury alone is known not to produce such malformations. When mitomycin-C treatment alone was performed on day 9.5 of pregnancy, only vertebral anomalies increased in incidence. Therefore, mitomycin-C teratogenicity in terms of the manifestation of cervical rib, polydactyly and tail anomaly, but not vertebral anomaly, was suggested to be enhanced by methylmercury. A considerable number of foetuses showed cleft palate involvement following combined treatments, but not by either chemical alone. Cleft palate is known to be a major malformation in mice that is caused by methylmercury, and mitomycin-C also induces cleft palate. Therefore, the two chemicals might have affected foetuses additively and thereby induced cleft palate.

Abnormalities, Drug-Induced↗
PubMed1986

Stability after freezing and thawing of solutions of mitomycin C in plastic minibags for intravesical use.

Solutions of 0.6 mg/ml mitomycin C (Mutamycin) in NaCl solution 0.9% in plastic minibags for intravesical use were stored at -20 degrees C and -30 degrees C and thawed by microwave radiation. Both unbuffered solutions and solutions buffered to approximately pH 7.5 were investigated. Concentrations were measured with HPLC. During freezing and storage at -20 degrees C sometimes crystallization of mitomycin C occurred. However, both buffered and unbuffered solutions could be frozen at -30 degrees C during at least four weeks and subsequently thawed without loss of content. Unbuffered mitomycin C solutions could be refrozen at -30 degrees C for another four weeks. Also buffered and unbuffered solutions of another brand of mitomycin C (Mitomycin-C Kyowa) could be frozen at -30 degrees C during four weeks without significant deterioration.

Administration, Intravesical↗
PubMed1985

In vitro chemosensitivity tests on human tumor xenografts by clonogenic assay: the combined use of mitomycin C with alpha-interferon or gamma-interferon.

Using the human tumor clonogenic assay technique, the effects of Mitomycin C plus either alpha-interferon or gamma-interferon were studied against five human tumor xenografts serially transplanted into nude mice (three gastric and two colon cancers). When the survival fraction found with the drug combination was smaller than the multiplication of survival fractions with either drug alone, the combined effect was defined as synergism. Similarly, antagonistic effect was defined when the survival fraction of drug combination was larger than the larger one observed in either interferon or Mitomycin C alone. Four out of five human tumor xenografts (three gastric and one colon cancers) showed synergistic effects in combination of alpha-interferon with Mitomycin C. Though two gastric cancer xenografts exhibited synergistic effects in combination of gamma-interferon with Mitomycin C, antagonistic effects, which was not found in combination of alpha-interferon with Mitomycin C, were observed in one gastric cancer and one colon cancer xenografts.

Adenocarcinoma↗
PubMed1988

Postoperative instillation of low-dose mitomycin C in the treatment of primary pterygium.

Eighty patients (99 eyes) with primary pterygia were treated with excision, with or without additional therapy, and were followed up for three to eight years after treatment. Of 29 eyes that underwent excision and postoperative instillation of 0.02% mitomycin C, there were only two recurrences. The other eyes were treated with excision only, excision and radiation, or excision and 0.04% mitomycin C. Instillation of 0.02% mitomycin C reduced the recurrence rate significantly (P less than .01). Only one of the 29 eyes (3%) treated with excision and 0.02% mitomycin C had a complication, the lowest rate of all groups postoperatively. We found the postoperative instillation of 0.02% mitomycin C, twice a day for five days, to be effective and safe in the treatment of primary pterygium.

Drug Administration Schedule↗
PubMed1983

Mitomycin-C-induced changes in the nucleoid of Escherichia coli K12.

The influence of low concentrations of mitomycin-C on the structure of the envelope-free nucleoid was studied in several strains of Escherichia coli K12. The wild-type strain AB1157 uvr+ rec+ and 3 mitomycin-C-sensitive derivatives carrying mutations in the uvrA, uvrB and recA genes, were used. Treatment of the control strain with mitomycin-C, 0.5 microgram/ml, followed by incubation in drug-free medium resulted in the formation of a transient fast-sedimenting nucleoid with a sedimentation coefficient of 2200 S. A fraction of 25% of the nucleoids had attained the normal sedimentation coefficient of 1570 S 3 h after removal of mitomycin-C. With the uvr- strains, mitomycin-C induced a slow, almost linear increase in the S value of the envelope-free nucleoid. In these cases the S value continued to increase during post-incubation and was 2050 S 3 h after removal of the drug. Post-incubation of recA- cells resulted in loss of supercoiling, decrease in S value of the nucleoid and degradation of DNA. Results obtained with phase-contrast and electron microscopy were in good agreement with the hydrodynamic data.

DNA Repair↗
PubMed1986

Use of intravesical cisplatin and mitomycin-C for recurrent transitional cell carcinoma of bladder refractory to thiotepa.

Superficial transitional cell carcinoma of the bladder (TCCaB) has a high incidence of recurrence. Intravesical thiotepa is the drug used most often for treatment. Intravesical mitomycin-C also has shown promise. Cisplatin has proven activity in patients with metastatic TCCaB and in experimental bladder cancer models. Patients who have no response to one intravesical agent such as thiotepa may respond to other agent(s) such as mitomycin-C or cisplatin. In this report we have evaluated 10 patients with superficial recurrent TCCaB who showed no response to intravesical thiotepa and were subsequently treated with mitomycin-C or cisplatin. Six patients were treated with cisplatin and 4 with mitomycin-C. The 4 treated with mitomycin-C had complete response or partial response within three months. Of the 6 treated with cisplatin, 4 had complete response within three months, and 2 had no response.

Biopsy↗
PubMed1984

The effect of inhibitors of macromolecular synthesis on neutrophil-mediated antibody-dependent cellular cytotoxicity: exacerbation by mitomycin C.

Previous work correlating 51chromium release with aggregate formation between neutrophils and target cells had indicated that unlike killing by lymphocytes, neutrophil-mediated antibody-dependent cellular cytotoxicity (NADCC) in the guinea-pig against hepatoma cells required that three or more neutrophils were simultaneously attached to the target cells. There was virtually no lysis when only one or two neutrophils were attached. This raised the possibility that the target cells could repair lesions inflicted by one or two cells and this was investigated using inhibitors of macromolecular synthesis. Actinomycin D, cycloheximide, puromycin and adriamycin had no effect--militating against a repair mechanism. Surprisingly, mitomycin C led to an exacerbation of NADCC. Chlorambucil, which like mitomycin C is an alkylating agent, had a similar effect though less marked. One explanation of this phenomenon which seemed likely was that the drugs were affecting the cell cycle of the target cells, i.e. that being alkylating agents they might be holding the target cells in a susceptible phase of the cycle. Experiments in which the target cells alone were preincubated with mitomycin C for varying periods of time (2-18 h) before the start of the assay, did not confirm this. However a thirty minute preincubation with mitomycin C of either the neutrophils or neutrophils plus the target cells resulted in increased cytolysis. The results indicate that the effect of mitomycin C in exacerbating NADCC is primarily on the neutrophil.

Animals↗
PubMed1989

Increased sensitivity of quinone resistant cells to mitomycin C.

L5178Y cells resistant to the model quinone antitumor agent, hydrolyzed benzoquinone mustard, were four-fold more sensitive to mitomycin C compared to parental cells. Mitomycin C also produced increased DNA-DNA crosslinking in these cells compared to parental L5178Y cells, but did not induce DNA double strand breaks in either cell line. The resistant cells have a 24-fold increased level of DT-diaphorase activity, an enzyme that produces two electron reduction of quinone groups. Dicoumarol, an inhibitor of DT-diaphorase, significantly inhibited crosslinking and cytotoxicity by mitomycin C in the quinone resistant cells. These findings suggest that DNA-DNA cross-linking may be a major contributor to mitomycin C cytotoxic activity in L5178Y cells, and that the hydroquinone of mitomycin C may play a major role in the crosslinking activity of this agent.

Animals↗
PubMed1989

Randomized clinical trial of mitomycin C as an adjunct to radiotherapy in head and neck cancer.

A randomized prospective clinical trial was carried out to assess the usefulness of the addition of mitomycin C to radiation therapy used alone or in combination with surgery for the treatment of squamous cell carcinoma of the head and neck region. One hundred and twenty patients with biopsy proven tumor of the oral cavity, oropharynx, larynx, hypopharynx, and nasopharynx were randomly assigned to receive or not receive mitomycin C; all other aspects were similar in the two treatment groups. One hundred and seventeen patients were evaluable with a median follow-up time of greater than 5 years. Acute and chronic normal tissue radiation reactions were equivalent in the two treatment groups. Hematologic and pulmonary toxicity were observed in the drug treated patients. Actuarial disease-free survival at 5 years was 49% in the radiation therapy group and 75% in the radiation therapy plus mitomycin C group, p less than 0.07. Local recurrence-free survival was 66% in the radiation therapy group and 87% in the radiation therapy plus mitomycin C group, p less than 0.02. The findings demonstrate that mitomycin C can be administered safely as an adjunct to radiation therapy in the treatment of head and neck cancer. The drug improves local tumor control without enhancing normal tissue radiation reactions.

Adult↗