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[Effects of mitomycin C perfusion after bladder tumor surgery].

In the last ten years, 26 cases of bladder tumor in T1-T2 stage have been given Mitomycin C perfusion in cava after operation to prevent tumor recurrence. The results of follow-up for one to eight years showed no recurrence occurred in all 26 cases with Mitomycin C perfusion and in control group (64 cases) 14 had recurrence. The authors consider that Mitomycin C perfusion in a long time is effective for the prevention of recurrence of bladder tumor. The methods and untoward effects of Mitomycin C perfusion are discussed in this article.

Administration, Intravesical↗

Arterial chemoembolization with mitomycin C microcapsules followed by transcatheter hepatic artery embolization for hepatocellular carcinoma.

Of 66 patients with hepatocellular carcinoma, 32 were treated by intraarterial injection of mitomycin C microcapsules (group A) and 34 patients by intraarterial injection of mitomycin C microcapsules followed by transcatheter hepatic artery embolization (group B). Measurable tumor regression greater than 50% in area on liver image occurred in 28% of group A and 57% of group B (p less than 0.05). A decrease of serum alpha-fetoprotein to less than half the initial level was demonstrated in 59% of group A and 91% of group B (p less than 0.05). The survival rate was better in group B compared with group A (p less than 0.05). These results indicate that arterial chemoembolization with mitomycin C microcapsules plus transcatheter hepatic artery embolization will be an improvement over arterial chemoembolization with mitomycin C microcapsules alone in the treatment of hepatocellular carcinoma.

Aged↗

Intraperitoneal mitomycin C in the treatment of peritoneal carcinomatosis following second-look surgery.

Persistent or recurrent peritoneal carcinomatosis (PC) documented at second-look surgery has proved relatively refractory to second-line therapy. The majority of these tumors do not respond to cisplatin based chemotherapy. Because of the relatively high response rate we observed with systemically administered mitomycin C plus 5-fluorouracil, we initiated a trial of intraperitoneal (IP) mitomycin C (10 mg/m2 in 2 L dialysate fluid every 4 weeks) in 14 patients with refractory PC secondary to gynecologic malignancies. All but one patient had PC secondary to ovarian cancer documented at second-look cytoreductive surgery following intense cisplatin based drug therapy. One patient had endometrial cancer and had been treated previously with radiation. In all, 49 courses of intraperitoneal mitomycin C were administered to 14 patients. Systemic toxicity was minimal, except for mild thrombocytopenia that occurred in four patients. However, abdominal pain due to chemical peritonitis was cumulative and dose limiting after three to five courses of therapy. Of the seven patients with measurable disease (positive serum CA-125 or intraperitoneal cytology), six had normalization of at least one of these two parameters. Eight of the 14 patients remain alive without clinical evidence of disease with a median follow-up duration of 10 months. We conclude that IP mitomycin C is a well-tolerated and potentially effective treatment modality in patients with limited PC following second-look surgical debulking for gynecologic malignancy.

Adenocarcinoma↗

Mitomycin C in the chemotherapy of advanced breast cancer.

Mitomycin C is a chemotherapeutic agent active against breast cancer. Because one of its potential toxicities is prolonged myelosuppression, it is not generally used in first-line chemotherapy regimens. However, several mitomycin C-containing combinations are effective in the salvage therapy of patients that have failed to respond to previous regimens. The choice of a salvage combination depends on the previous treatment received by an individual patient. Patients failing regimens based on CMF (cyclophosphamide, methotrexate, 5-fluorouracil [5-FU]) should be treated with combinations incorporating drugs not included in CMF. Active agents in this setting include mitomycin C, doxorubicin, and vinca alkaloids (usually vinblastine). Patients treated with combinations based on doxorubicin and cyclophosphamide (AC) are frequently administered a CMF-type regimen after a cumulative dose of doxorubicin has been reached. Therefore, they have often received doxorubicin, cyclophosphamide, methotrexate, and 5-FU. Salvage chemotherapy for failing patients in this setting is generally based on mitomycin C and/or vinblastine. Selection of a chemotherapeutic regimen for breast cancer must take into account the palliative nature of chemotherapy in this disease. Consequently, effective combinations that can be administered with minimal disruption of a patient's life-style are preferred.

Antineoplastic Combined Chemotherapy Protocols↗

Intraoperative chemotherapy with carbon particles adsorbing mitomycin C for gastric cancer with peritoneal dissemination in rabbits.

A new dosage form of activated carbon particles adsorbing mitomycin C (MMC-CH) was studied for its therapeutic effects on peritoneal dissemination in both animal experiments and preliminary clinical trials. Rabbits with peritoneal dissemination induced by intraperitoneal transplanted VX2 carcinoma were used as experimental models. Seven days after intraperitoneal transplantation of VX2 carcinoma, mitomycin C at 1 mg/kg in the form of MMC-CH or at 0.185 mg/kg in the form of mitomycin C aqueous solution was given intraperitoneally. The two doses were equal in toxicity. MMC-CH extended survival time statistically significantly longer than did mitomycin C aqueous solution. Preliminary clinical trial with MMC-CH has been made in eight patients with gastric cancer and peritoneal dissemination, with no control group. MMC-CH, 60 to 100 mg/person, was given intraperitoneally before the surgical wound was closed. Patients were observed for more than 1 year. Five of the eight patients survived more than 1 year, and the mean survival time was 13.9 months, whereas in the patients treated previously without MMC-CH the 1-year survival rate was 17% and the mean survival time was 6.5 months. Side effects were temporary and tolerable.

Adsorption↗

Occurrence of cytosolic protein and phosphoprotein changes in human colon tumor cells with the development of resistance to mitomycin C.

The cytosolic proteins and phosphoproteins of a mitomycin C-sensitive cell line were examined as progressively greater doses of mitomycin C were administered over a period of 44 weeks. Resistance of the human colon carcinoma cell line increased from a 50% inhibitory concentration of 1 to 6 microM over this time period. Changes in cytosolic protein patterns included increases in the amounts of three proteins with molecular weight X 10(-3)/apparent isoelectric point (Mr/pl) values of 56/6.2, 37/7.3, and 27/6.1. Analysis of in vitro 32P-labeled phosphoprotein patterns revealed reductions in the amounts of four proteins with Mr/pl values of 42/6.3, 40/6.7, 31/6.3, and 25/6.1. One increase was detected in a phosphoprotein with a Mr/pl value of 33/6.1. These changes in cytosolic components paralleled the development of resistance to mitomycin C and may reflect changes in the clonal composition of the cell line as it becomes progressively more resistant to mitomycin C or changes in critical proteins or enzymes involved in the activation or biotransformation of the drug.

Autoradiography↗

Effect of human fibroblast interferon on the antiviral activity of mammalian cells treated with bleomycin, vincristine, or mitomycin C.

Bleomycin, vincristine, or mitomycin C, when added to HeLa cells simultaneously with human fibroblast interferon (IFN-beta), caused a decrease in cell density and inhibited DNA synthesis compared with HeLa cells treated with IFN-beta alone. However, the IFN-beta-induced antiviral processes were unaffected by the presence of these drugs as determined by in vitro enzyme assays and the development of the antiviral state in the intact HeLa cell. HeLa cells treated with IFN-beta alone or with IFN-beta in combination with bleomycin, vincristine, or mitomycin C were able to induce the double-stranded RNA-dependent adenosine triphosphate:2',5'-oligoadenylic acid adenyltransferase (EC 2.2.2.-) and the double-stranded RNA-dependent protein kinase. Furthermore, the antiviral state as measured by the reduction of plaque-forming units after infection of treated cells (with IFN-beta alone or with IFN-beta plus drugs) with vesicular stomatitis virus was not affected. These results indicate that, under these experimental conditions, the double-stranded RNA-dependent adenosine triphosphate:2',5'-oligoadenylic acid adenyltransferase and protein kinase can be induced by IFN-beta in cells treated with bleomycin, vincristine, or mitomycin C. These cells also develop the antiviral state. These experiments could provide a basis for a careful examination of the effects of interferon on the development of the antiviral state when testing potentially active antineoplastic agents. The possibility that IFN-beta potentiates the cytotoxic effects of bleomycin and mitomycin C on HeLa cells is also discussed.

Antibiotics, Antineoplastic↗

Enhancement of the cytocidal effect of mitomycin C by means of simultaneous administration of prostaglandin E1.

The blood supply in the central portions of solid Yoshida sarcoma tumors is poor, but these portions contain viable cells capable of tumor growth when transplanted into new hosts. Attempts were made to increase penetration into these portions in rats by an injection of prostaglandin E1 together with lissamine green dye (used as a marker of drug penetration). The lissamine green dye defined the regions which could not readily be reached by blood-borne substances. Next, mitomycin C in place of lissamine green was administered together with prostaglandin E1. The growth of Yoshida sarcoma cells transplanted subcutaneously was suppressed significantly in the rats given mitomycin C with prostaglandin E1 compared with that in the rats given mitomycin C alone. The effect was greater when prostaglandin E1 was administered by an intraarterial route than by an intravenous route (P less than 0.01). Five patients with hepatic metastases from colorectal carcinoma were treated with a one-shot infusion of mitomycin C together with prostaglandin E1. Two patients showed objective evidence of improvement.

Alprostadil↗

Mitomycin C-induced acceleration of liver cell polyploidization in adult rat after partial hepatectomy.

Mitomycin C, a DNA cross-linking agent, was administered for a week intraperitoneally to a normal 9-week-old rat in which hepatocyte proliferative activity had almost ceased. In the rat treated with mitomycin C, the number of polyploid cells with the DNA amounts more than 4C was not increased in comparison with that in the control rat without any treatment. However, the partial hepatectomy in the rat pretreated with mitomycin C provoked prominent hepatocyte polyploidization much greater in degree than that found in the hepatectomized rat without mitomycin C treatment. These results seem to indicate that the existence of cross-linking DNA damages is a latent factor necessary for the induction of abortive mitosis of a cell after completion of DNA synthesis, which results in the production of a mononuclear polyploid cell in one-step higher DNA class. Cross-linking DNA damages and DNA synthesis are the essential factors for the manifestation of polyploidization.

Animals↗

Induction by mitomycin C of recA protein synthesis in bacteria and spheroplasts.

The effect of mitomycin C on the synthesis of recA protein in Escherichia coli has been analyzed in a variety of conditions, using an immunoradiometric assay (Paoletti, C., Salles, B., and Giacomoni, P. U. (1982) Biochimie 64, 239-246). In exponentially growing cultures of E. coli AB 1157, the addition of mitomycin C (5 micrograms/ml) promotes a 15-fold increase of the content of recA protein with respect to the basal level. Kinetic analysis of this induction shows that the maximum is reached 60 to 90 min after the addition of the drug and then the level decreases. In an uvrA mutant treated with mitomycin C the level of recA protein reaches a maximum within an hour and afterwards it does not decrease. Treatment of exponentially growing cells with EDTA and lysozyme induces a 3-fold increase of recA protein content, in comparison to the basal level. When such spheroplasts are added with mitomycin or nalidixic acid, a striking increase of the recA protein content in the spheroplast suspension is observed, which tends to level off an hour and a half after the addition of the drugs. The maximum level of recA protein content is five times the level measured after lysozyme treatment, i.e. 15 times the basal level in exponentially growing cells.

Antibiotics, Antineoplastic↗

Toxicity of mitomycin C and anti-intoxication by fumaric acid in liver and kidney cellular fine structure.

The previous study indicated that the toxic symptoms in ICR mice given two ip injections of 4 mg/kg of mitomycin C at an interval of 48 hr were reduced by the concurrent administration of 40 mg/kg of fumaric acid. In the present study, are described the changes of subcellular components and organella in the liver and kidney at 4 days after the 2nd injection. The liver treated with mitomycin C showed perinuclear irregularity, aggregation of chromatins, and abnormal cytoplasmic organella (e.g., swelling of mitochondria and dilatation of rough endoplasmic reticulum). Focal localization of rough endoplasmic reticulum was noted. The concurrent administration of fumaric acid reduced the incidence of such deleterious changes. Increases in the number of nucleoli and normal cytoplasmic organella were evident. The kidney treated with mitomycin C showed decrease of chromatins and edematous nuclear matrix. The cytoplasmic organella were swollen. The action of fumaric acid against mitomycin C intoxication was more apparent in the kidney. Chromatins and nucleoli developed well and other subcellular organella appeared completely normal.

Animals↗

[Studies on the physiological disposition and pharmacokinetics of 7-N-(p-hydroxyphenyl)-mitomycin C].

A new mitomycin derivative, 7-N-(p-hydroxyphenyl)-mitomycin C (KW 2083), was labeled with 14C at 3 and 5 position of p-hydroxyphenyl moiety. Its radioactive purity and specific radioactivity were 97.6% and 3.42 mu Ci/mg, respectively. The labeled drug was administered intravenously to male rats or pregnant rats. Radioactivity was rapidly cleared from the plasma and transferred to the peripheral tissues. However low and sustained level of radioactivity was maintained in the plasma, even 48 to 72 hours after administration. About 29% of the radioactivity was recovered from the urine and 58% from the feces by 72 hours after administration. In the bile, 45% of the dose was excreted until 48 hours after administration, and the enterohepatic circulation was observed. The tissue levels of 14C-KW 2083 given to male rats were highest in the kidney, liver and intestinal contents. In the brain, eyes and spinal cord the radioactivity was very low. Autoradiography with 14C-KW 2083 in male or pregnant rats demonstrated that radioactivity distributed in kidney, liver and intestinal contents. The transfer of radioactivity was very low in the fetuses of rats. Radioactivity was observed to some extent in the fetal membrane. Plasma concentrations of KW 2083 or mitomycin C in dogs were determined by means of bioactivity and could be best described by a two-compartment open model. The total clearance of KW 2083 was higher than mitomycin C and hence the biological half life of KW 2083 was shorter. The result may suggest less toxicity of KW 2083 to the host cells.

Animals↗

Incidence of late-onset bleb-related complications following trabeculectomy with mitomycin.

OBJECTIVES: To determine the incidence of late-onset bleb-related complications following trabeculectomy with mitomycin and to report the management and outcome of bleb leaks following trabeculectomy with mitomycin. METHODS: A retrospective medical record review of all patients who underwent trabeculectomy with mitomycin from June 1, 1991, through April 30, 1998, at our institution was performed. The Kaplan-Meier survival method was used to estimate the probability of (1) endophthalmitis, (2) blebitis, (3) a bleb leak, and (4) the combined outcome (the first occurrence of a bleb leak, blebitis, or endophthalmitis). This survival analysis included only the first trabeculectomy in an eye, with at least 3 months of follow-up during the study period. A separate description of bleb leak management and outcome was performed. RESULTS: Two hundred thirty-nine eyes of 198 patients were included in the survival analysis. The average follow-up was 2.7 (range, 0.3-7.3) years. Twenty eyes (8%) from 19 patients experienced a bleb leak; the adjusted incidence was 3.2% per patient-year. Five eyes (2%) had an episode of blebitis. Eight eyes (3%) experienced an episode of endophthalmitis; the follow-up adjusted incidence (number of events per patient-year) was 1.3%. Twenty-seven eyes (11%) from 26 patients had at least 1 of the complications of a bleb leak, blebitis, or endophthalmitis; the adjusted incidence was 4.4% per patient-year. A Kaplan-Meier analysis estimated the 5-year probability of developing a bleb leak, blebitis, or endophthalmitis to be 17.9%, 6.3%, and 7.5%, respectively. Two hundred fifty-eight trabeculectomies in 242 eyes of 198 patients were included in the description of bleb leak management and outcome. Bleb leaks occurred in 22 eyes (9% of the 258 trabeculectomies). Seventeen eyes were successfully treated with office-based measures, and 4 ultimately underwent surgical bleb revision. One eye without infection continued to leak after 11 months of office-based therapy. CONCLUSIONS: There is significant morbidity associated with a trabeculectomy with mitomycin. The incidence of a bleb leak or an infection continues at a fairly constant rate over time, such that at 5 years, up to 23% of all patients might develop one of these complications. An isolated bleb leak seems to be a relatively benign condition, as three quarters resolve with office-based methods.

Adolescent↗

Topical mitomycin application after laryngotracheal reconstruction: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To explore the effect of mitomycin treatment on the pediatric airway following laryngotracheal reconstruction. DESIGN: Randomized, double-blind, placebo-controlled trial. PATIENTS: Children aged 2 to 17 years with subglottic or upper tracheal stenosis undergoing laryngotracheal reconstruction at a single, tertiary care, children's hospital. INTERVENTION: At the time of extubation or stent removal, the children underwent bronchoscopy and 0.4 mg/mL (2 mL of a 0.2-mg/mL solution of either mitomycin or an equal volume of isotonic sodium chloride was directly applied to the subglottic region for a single application of 2 minutes. These children then underwent interval endoscopy at 2 weeks, 6 weeks, and 3 months postoperatively for assessment of their airways. RESULTS: Granulation tissue was graded on a scale of 0 (none) to 4 (near-total or total occlusion). Videotapes of endoscopies were independently observed and graded by 3 pediatric otolaryngology fellows with a subsequent interobserver agreement of 91.6%. The results were then dichotomized to represent a single cohort in which further surgical intervention would be required and another separate cohort in which further surgery would not be required. At the 1-year mark, interim analysis was performed by a Data Safety and Monitoring Committee. At this time, 13 children had been randomized to the mitomycin-treated arm of the study and 11 children to the placebo-treated arm. A 2-tailed Fisher exact test revealed a value of 1.00. The Data Monitoring and Safety Committee advised that the trial should be stopped because the distributions between the 2 populations were almost identical. CONCLUSION: We cannot reject the null hypothesis that a single topical dose of mitomycin exerts an equal benefit as does isotonic sodium chloride when applied to the pediatric airway after laryngotracheal reconstruction.

Administration, Topical↗

Surgical management of choanal atresia: improved outcome using mitomycin.

OBJECTIVE: To evaluate the intraoperative use of mitomycin to improve the surgical outcome and reduce the rate of soft tissue restenosis in children undergoing choanal atresia repair. DESIGN: Retrospective chart review of all patients surgically treated for congenital choanal atresia by the senior author (W.F.M). SETTING: Tertiary children's hospital. PATIENTS: Eight consecutive patients with bony choanal atresia (6 unilateral and 2 bilateral) were compared with 15 historical controls (6 unilateral and 9 bilateral). All study and historical control patients were treated with soft plastic postoperative stenting. INTERVENTION: At the completion of the surgical repair of the choanal atresia, 0.4 mg/mL of topical mitomycin was applied to the posterior choanae for 3 minutes. MAIN OUTCOME MEASURE: The success rate of the repair of the choanal atresia as determined by the postoperative need for dilation or revision surgical procedures was compared with that of the historical controls. RESULTS: All 8 children with intraoperative use of mitomycin were treated with a mean +/- SEM of 0.375 +/- 0.183 dilations per patient. The 15 children in the control group received a mean +/- SEM of 3.667 +/- 0.583 postoperative dilations for soft tissue restenosis. The difference in the number of postoperative dilations between the study and control group was statistically significant (P =.006) using a t test. CONCLUSIONS: Mitomycin is an effective and reliable treatment for improving the surgical outcome for choanal atresia repair. This may obviate the need for postoperative dilations and may potentially eliminate the need for surgical stenting.

Administration, Topical↗

Topical mitomycin as an adjunct to choanal atresia repair.

OBJECTIVE: To evaluate the use of topical mitomycin in choanal atresia repair to reduce the development of granulation tissue and cicatrix. DESIGN AND SETTING: Retrospective case series in 2 tertiary care centers. PATIENTS: Twenty patients with either unilateral or bilateral congenital choanal atresia underwent repair using the transnasal endoscopic approach, the transpalatal approach, or both. INTERVENTIONS: The surgeons favor the use of the endoscopic transnasal drillout technique for all unilateral cases of choanal atresia and for selected bilateral cases. We describe our experience and treatment paradigm for these 20 patients (15 with unilateral atresia, 5 with bilateral atresia). Topical application of mitomycin was used, and in some cases postoperative stenting, for a period of 1 to 2 weeks. In 8 cases, a second application of mitomycin was used. Follow-up ranged from 3 months to 2 years (mean, 9 months). OUTCOME MEASURE: The patency of the choanae without respiratory distress or nasal drainage, as assessed by endoscopic evaluation, determined a successful repair. RESULTS: Of the 20 patients, 17 retained patent airways. Three patients experienced improvement from a total atresia to a narrowed, stenotic choana. CONCLUSIONS: The use of mitomycin as an adjunct to the surgical repair of choanal atresia may offer improved patency with a decreased need for stenting, dilatations, and revision surgery. Newer endoscopic techniques with powered instrumentation further enhance the safety and efficacy in the repair of choanal atresia.

Administration, Topical↗

The role of mitomycin in the prevention and treatment of scar formation in the pediatric aerodigestive tract: friend or foe?

OBJECTIVE: To evaluate the role of mitomycin in the prevention and treatment of scar formation in the pediatric aerodigestive tract. DESIGN: Prospective study; institutional review board-approved clinical trial. SETTING: Tertiary care pediatric medical center. PATIENTS: Fifteen patients; choanal atresia in 5 patients, airway stenosis in 8 patients, hypopharyngeal stenosis in 1 patient, and esophageal stenosis in 1 patient. OUTCOME: The efficacy and safety of mitomycin in the prevention of scar formation. INTERVENTION: All patients underwent surgical repair of the stenotic area, followed by topical application of mitomycin (1 mL of 0.4 mg/mL) for 4 minutes. RESULTS: Ten patients (67%) showed major improvement, 4 patients (27%) showed minor improvement, and 1 patient (7%) showed no improvement. CONCLUSION: Topical application of mitomycin can play an effective role in the prevention and treatment of scar formation in the aerodigestive tract.

Administration, Topical↗

Superselective intra-arterial chemotherapy with mitomycin C in hepatic metastases from colorectal cancer.

BACKGROUND: Mitomycin C has been found clinically useful in the treatment of colorectal cancer when administered via the hepatic artery. In a prospective therapeutic trial, we studied the effect of superselective intra-arterial chemotherapy with mitomycin C in patients with hepatic metastases from colorectal cancer. METHODS: Forty-six patients with hepatic metastases from colorectal cancer received intra-arterial chemotherapy with mitomycin C (SIAC) between 1981 and 1991. The results of a 5-year follow-up were compared with 46 control patients standardized by sex, age, and tumor distribution. RESULTS: The overall response rate to intra-arterial chemotherapy was 20%. The median survival time for responders was 26 months and that for nonresponders 12 months (P < 0.003). The median survival period after intra-arterial chemotherapy was 15 months, compared with 9 months in controls (P < 0.004). The cumulative 5-year survival rate was 6% for patients treated by SIAC and 5% for controls. Cessation of chemotherapy was necessary in 39 of the 46 patients: in 28 because of tumor progression, in 9 because of toxicity, in 1 because of catheterization difficulties, and in 1 because of patient refusal. CONCLUSIONS: Superselective intra-arterial mitomycin C therapy had a poor effect on hepatic metastases from colorectal cancer because of the low response and long-term survival rates.

Adult↗