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PubMed1977

Mitomycin antibiotics. Synthesis and activity of 1,2-disubstituted mitosenes.

cis-1-Acetamido-2-acetoxy-7-methoxy-N-methylmitosene was prepared in 11 steps from 7-methoxy-6-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-one by a route involving bromination of the pyrrolidineenamine or trimethylsilyl enol ether of starting material, displacement of bromide by acetate, oxime formation, and reductive acetylation, followed by elaboration of the quinone and methyl carbamate functions according to previously established methods. An unsubstituted carbamate could not be prepared. The mitosene thus synthesized differs from previously reported 1,2-disubstituted mitosenes, which are derived from the solvolysis of mitomycins, in that it has the opposite arrangement of oxygen and nitrogen substituents at the 1 and 2 positions. It showed antibacterial activities in disk-plate assays superior to those of cis-diacetylapomitomycin A and equivalent to those of certain 1-substituted mitosenes; however, it was less active than mitomycin A in these assays. It was inactive in inducing lambda-bacteriophage in Escherichia coli and inactive against P388 leukemia in mice. In contrast, certain 1-substituted mitosenes were active in prophage induction and 2b and mitomycin A were active in both assays.

Animals↗
PubMed1983

Mitomycin C and porfiromycin analogues with substituted ethylamines at position 7.

A series of 7-(2-substituted-ethyl)amino analogues of mitomycin C and porfiromycin was prepared and screened in standard antitumor systems. Certain of these analogues showed better activity than mitomycin C against P-388 leukemia, L-1210 leukemia, and/or B-16 melanocarcinoma in mice. Compounds also tested for their leukopenic effects in mice, the limiting toxicity of mitomycin C. Some of them were less leukopenic and some were more leukopenic than this clinical agent. No statistically significant correlations could be made between physicochemical properties and antitumor activities of the analogues.

Animals↗
PubMed1983

Mitomycin C analogues with secondary amines at position 7.

A series of mitomycin C analogues with secondary amines at position 7 was prepared from mitomycin A. Eleven of the 20 new compounds in this series were more active than mitomycin C against P-388 murine leukemia, and 2 of these 11 were significantly less leukopenic. The two substituents conferring these superior properties were 4-formylpiperazine and 2-cyanoaziridine. No quantitative correlations could be made among antitumor activities and physicochemical properties of the analogues, although the relative ease of quinone reduction might be related to the good potencies (minimum effective doses) of many of them.

Animals↗
PubMed1987

Preparation and antitumor activity of new mitomycin A analogues.

A series of 26 mitomycin A analogues including 23 new ones was prepared by a variety of methods. The most useful methods were alkoxide exchange on mitomycin A and treatment of 7-hydroxymitosane with 3-substituted 1-phenyltriazenes. Many of the new analogues were superior to mitomycin C in the P388 leukemia assay and the more stringent subcutaneous B16 melanoma assay both in mice. Four of them gave long-term survivors in the latter assay. Quantitative correlations between log P and antitumor activity were not possible, but some guidelines for future analogue development are proposed.

Animals↗
PubMedDate not supplied

Ocular hypotony after laser suture lysis following trabeculectomy with mitomycin C.

BACKGROUND: To report our experience with laser suture lysis (LSL) following trabeculectomy with mitomycin C, its timing, effectiveness and related complications. METHODS: We retrospectively examined 38 consecutive eyes of 36 patients that underwent LSL following trabeculectomy with mitomycin C. RESULTS: The mean preLSL intraocular pressure (IOP) was 27.0 mm Hg (SD 6.3, range 16-39 mm Hg) and the postLSL IOP (IOP 1 h after the last session of LSL) was 16.0 mm Hg (SD 7.2, range 3-31 mm Hg). Following the LSL in 7 eyes (7 of 38) hypotony (IOP<6 mm Hg, lasting more than 24 h) developed. Two groups were defined. In group I no hypotony was found after LSL and group II went through a period of hypotony. The time interval between surgery and LSL was significantly shorter in group II (mean 5.7, SD 7.5, range 1-19 days), compared to group I ( mean 14.7, SD 13.0, range 1-44 days) (p=0.041). The mean final IOP (IOP measured at the last visit) was 13.3 mm Hg (SD 3.4, range 6-20 mm Hg) and mean follow-up was 6.1 months (SD 3.9, range 2.0-15.2 months). No hypotony was found at final examination. PostLSL IOP and final IOP were significantly lower in group II (p=0.002 and p=0.024 respectively). IOP reduction by LSL was significantly greater in group II (p=0.046). CONCLUSION: LSL is an effective and safe procedure to lower the IOP following trabeculectomy with mitomycin C. Early application of LSL results in lower final IOPs, but has a higher risk of hypotony.

Adolescent↗
PubMed1999

The effect of intravesical mitomycin C on the recurrence of superficial (Ta-T1) bladder cancer. A Hungarian Multicenter Study.

We evaluated the prophylactic efficacy of instillations of intravesical mitomycin C in 57 patients with primary superficial bladder cancer in a multicenter clinical trial. After complete transurethral resection of Ta-T1 G1-G2 transitional cell bladder carcinomas, patients were treated with mitomycin 40 mg/50 ml saline of 15 instillations for 12 months. Most of the complications were mild and transient but two patients dropped out of the trial because of moderate side effects. Fifty-one patients were evaluable. We observed tumour recurrences in six patients (11.8%) during a median follow-up of 44.5 months. The recurrences were treated by transurethral resection. There was no muscle invasive progression in the recurrences. Our investigations confirm the effectiveness of mitomycin C in the treatment of patients with superficial bladder cancer.

Administration, Intravesical↗
PubMed1997

A better therapeutic profile for the combination of mitomycin-C, ifosfamide and cisplatin (MIC) in advanced non-small-cell lung cancer: a useful dose-schedule modification.

BACKGROUND: In our previous experience with chemotherapy for non-small-cell lung cancer (NSCLC) the combination of mitomycin, ifosfamide and cisplatin (MIC) showed the highest activity in a three-arm randomized trial; the MIC regimen also yielded the most toxic effects, with 8% WHO grade 2-4 nephrotoxicity, 21% grade 3-4 leukopenia and 10% grade 3-4 thrombocytopenia. In that study cisplatin (120 mg/m2) was delivered on day 1 and ifosfamide and mitomycin on day 2. In an effort to reduce MIC toxicity a modified regimen was tested in a phase II trial: cisplatin 100 mg/m2 was given on day 2 and ifosfamide on day 1 with mitomycin. PATIENTS AND METHODS: From November 1993 to December 1995, 70 advanced NSCLC patients entered the trial. RESULTS: Twenty-nine of 70 patients achieved major response (41%) with 6 complete (9%) and 23 partial remissions (33%). We recorded 4% of WHO grade 3-4 anemia, and 2% of leukopenia and thrombocytopenia. CONCLUSION: We confirmed the activity of the MIC regimen in NSCLC, and the modified schedule seems to substantially improve the safety of the combination.

Adult↗
PubMed2002

Influence of intraperitoneal therapy with mitomycin C adsorbed on activated carbon on anastomotic and wound healing in rats.

In an effort to prevent intraperitoneal dissemination of gastric carcinoma, local chemotherapy with mitomycin C adsorbed to activated carbon (MMC-CH) has been implemented. Results of clinical studies showed improved survival and a reduced systemic toxicity after the use of prophylactic treatment with MMC-CH. A significantly higher rate of intraperitoneal septic complications following MMC-CH therapy was found. The aim of this study was to assess whether intraperitoneal MMC-CH affects wound healing or healing of intestinal anastomoses. Standardized laparotomy was performed in 77 rats. The examinations were performed in 27 animals in the control group, 24 animals in the charcoal group, and 26 animals in the MMC-CH group. The animals and groups were distributed randomly. After an ileal anastomosis was performed, MMC-CH, charcoal, or sodium chloride 0.9% was administered intraperitoneally. After 10 days, collagen content as well as bursting strength/pressure of the fasciotomy and the anastomotic site was examined. Body weight and blood parameters analyzed included hemoglobin level, white blood cell count, platelet count, and total protein. Concerning body weight and hematology, no significant changes were observed. Three of 26 animals in the MMC-CH group, 2/24 in the charcoal group and 1/27 in the control group developed an anastomotic leakage. The bursting pressure of the anastomoses and the bursting strength of the fasciotomy as well as the relative collagen content did not differ significantly after treatment with charcoal or mitomycin C compared to the control group. Local inflammation consisting of charcoal-laden granulomas was detected histologically in the MMC-CH group and to a lesser extent in the charcoal group. In conclusion, no significant influence of intraperitoneal mitomycin C adsorbed on activated charcoal, in terms of its effect systemically or its effect on wound healing, could be demonstrated as a result of slow release. Histological changes seen with the use of activated charcoal suggest that perhaps a more ideal absorbable carrier should be sought.

Adsorption↗
PubMed2001

Autologous blood injection for marked overfiltration early after trabeculectomy with mitomycin C.

PURPOSE: After trabeculectomy with mitomycin C, extremely low intraocular pressure (IOP) with excess filtration may cause hypotonous maculopathy in the early postoperative period. We evaluated the effect of injecting autologous blood on reversing early postoperative marked hypotony after trabeculectomy with mitomycin C. METHODS: Trabeculectomy with mitomycin C was performed in 258 eyes between 1994 and 1998. Peribleb autologous blood injection was performed in five eyes in which pressure patches were ineffective in reversing excess filtration. Approximately 0.1 to 0.3 ml of whole unclotted blood was slowly injected at least 3 mm from the edge of the flap using a sterile 27-gauge needle. RESULTS: None of these eyes developed hypotonous maculopathy after injection. After a mean 31-month follow-up, all eyes had well-controlled IOP and visual acuity in three eyes was much improved. Postoperative complications included mild IOP elevation in one eye treated with laser suturelysis, and fibrinous pupillary membrane in one eye. CONCLUSION: In the early postoperative period, autologous blood injection is effective in reversing excess filtration.

Aged↗
PubMed1996

Effective treatment of advanced breast cancer with vinorelbine, mitomycin C plus human granulocyte colony-stimulating factor.

A phase II trial was performed to evaluate the efficacy and tolerance of vinorelbine (VNB), mitomycin C (MMC), and recombinant human granulocyte colony-stimulating factor (G-CSF) in advanced breast cancer. Between October 1992 and July 1994, 55 patients entered this trial. Nine patients had locally advanced disease and 46 had distant metastases, including 14 who had received previous palliative chemotherapy with (n = 9) or without anthracyclines (n = 5). Therapy consisted of VNB 40-50 mg m(-2) diluted in 250 ml saline infused over 30 min every 3 weeks, and MMC 15 mg m(-2) administered by intravenous bolus injection every 6 weeks. G-CSF was given at 5 microg kg(-1) day(-1) subcutaneously from days 2 to 7 following each cytotoxic drug administration. Treatment was continued in case of response or stable disease for a total of six courses. The overall response rate was 73% for all 55 patients (95% confidence interval, 59-84%), including 12 (22%) complete response (CR) and 28 (51%) partial response (PR); 13 patients (24%) had stable disease (SD), and only two (4%) progressed. All nine patients with locally advanced disease were rated responsive (two pCR, seven PR) and underwent surgery with curative intent. Eight out of nine remain disease free after a median observation period of 18 months (range, 13.5-28 months). Among the 32 previously untreated patients with metastatic disease, nine (28%) achieved CR, 15 PR (47%), seven SD (22%) and one PD (3%). Second-line chemotherapy with this regimen resulted in 7/14 (50%) objective remissions (one CR, six PR), six had SD and one PD. The median time to progression was 12 months (range, 2-24+ months) in previously untreated patients with disseminated disease, and 6.0 months (range, 2-22 months) in those who had failed prior chemotherapy. After a median follow-up time of 20 months, 24 patients with distant metastases are still alive with disease; median survival has not been reached yet. The dose-limiting toxicity was myelosuppression: six (11%) and ten patients (18%) had World Health Organization grade 3, and eight (14%) and nine patients (16%) had grade 4 leucopenia and granulocytopenia respectively. Severe (WHO grade 3) non-haematological toxicities included nausea/vomiting in 7%, constipation in 9%, peripheral neuropathy in 5%, infectious episodes in 7%, phlebitis due to drug extravasation in 5%, alopecia in 9%, and acute reversible pulmonary toxicity in 11%. Our data suggest that vinorelbine, mitomycin C plus G-CSF has an excellent anti-tumour activity in advanced breast cancer, probably superior to most other available combination chemotherapy regimens. This combination does not seem to present significant cross-resistance with previous CMF or anthracycline regimens. Apart from reversible, acute pulmonary toxicity, a rare adverse reaction that had previously been described for VNB, as well as the combination of natural vinca alkaloids with mitomycin C, and few episodes of grade 3 neurotoxicity (all of which occurred at the initial 50 mg m(-2) VNB dose level), the tolerance of this regimen seems acceptable and justifies further evaluation in front-line and salvage therapy of advanced breast cancer.

Adult↗
PubMed1997

Preliminary results of the use of intraperitoneal carbon-adsorbed mitomycin C in intra-abdominal malignancy.

Eleven patients suffering from intra-abdominal malignancy were treated with various doses of intraperitoneal mitomycin C adsorbed onto activated carbon particles. Seven of the patients underwent resection of their primary gastric tumour and all developed potentially life-threatening severe complications that proved to be fatal in four patients. The pattern of complications seen in these patients was unusual in patients undergoing gastrectomy and must be presumed to be secondary to the intraperitoneal mitomycin C. Intraperitoneal mitomycin C at a dose of 25 mg and 50 mg in the presence of an anastomosis or other suture line does not appear to be safe.

Adenocarcinoma↗
PubMed1997

Conjunctival autograft versus topical mitomycin C in treatment of pterygium.

A prospective study was carried out to assess the recurrence rate of pterygium with conjunctival autograft versus the use of topical mitomycin C. In 27 eyes undergoing pterygium excision with conjunctival autograft, the recurrence rate was found to be 25.9% after 1 year mean follow-up. In the second group of 32 eyes, pterygium was removed using the bare sclera method. All these patients received post-operatively 0.2 mg/ml (0.02%) topical mitomycin C twice a day for 5 days. At 1 year mean follow-up, the recurrence rate in this group was 9.4%. Although the difference was not statistically significant, the number of recurrences was lower in the mitomycin-C-treated group than in patients undergoing conjunctival autograft.

Adult↗
PubMed2002

Infusional 5-fluorouracil, cisplatin and mitomycin C in advanced gastric cancer: a low cost effective regimen.

Recently, we reported a highly active regimen in advanced gastric cancer including a weekly administration of cisplatin, epidoxorubicin, leucovorin, 5-fluorouracil with the support of filgrastim. In order to simplify the administration and to decrease the toxicity of these drugs, mainly epidoxorubicin-induced alopecia, we designed a regimen including an infusional 5-fluorouracil schedule according to the de Gramont regimen, cisplatin and mitomycin C replacing epidoxorubicin. Forty-five patients with advanced or metastatic gastric cancer were treated with cisplatin 50 mg m(-2) i.v. on day 1, every 2 weeks, 6S-stereoisomer-leucovorin 100 mg m(-2) i.v. followed by 5-fluorouracil 400 mg m(-2) i.v. bolus and 600 mg m(-2) i.v. in a 22-h infusion, on days 1 and 2, every 2 weeks, and mitomycin C 7 mg m(-2) i.v. bolus on day 2, every 6 weeks. Grades 3-4 toxicities (National Cancer Institute-Common Toxicity Criteria) consisted mainly of neutropenia and thrombocytopenia. Five patients had a complete response and 16 had a partial response for an overall response rate of 46.7% (95% confidence interval, 32.1-61.2%). The median survival was 11 months. The combination of cisplatin, 5-fluorouracil and leucovorin according to de Gramont, and mitomycin C seems to be an active and safe regimen in the treatment of advanced gastric cancer. Because of its low cost it may be suggested for patients not enrolled into clinical trials.

Adult↗
PubMed2004

Capecitabine in combination with mitomycin C in patients with gastrointestinal cancer: results of an extended multicentre phase-I trial.

The aim of this study was to determine the dose-limiting toxicity (DLT) and establish the recommended dose for mitomycin C added every 3 weeks to the standard combination dose of capecitabine. Cohorts of at least three patients with pretreated gastrointestinal carcinoma received capecitabine 1000 mg m(-2) orally twice daily on days 1-14 plus i.v. bolus mitomycin C on day 1 at doses of 4, 6, 8 or 10 mg m(-2) (corresponding to dose levels I-IV). Cycles were repeated every 3 weeks. Two treatment cycles were considered for the evaluation of DLTs. Of the 53 patients enrolled, the majority had colorectal (n=27) or gastric (n=14) cancers. Patients had received a median of two lines of prior chemotherapy (34% with >/=3 lines and 87% with prior 5-FU-based therapy). At the recommended dose level (IV, n=30), grade 3 adverse events during cycles 1 and 2 were: anaemia (10%); leukopenia (3%); thrombocytopenia (3%); stomatitis/mucositis (3%); hand-foot syndrome (3%). Two patients experienced DLTs (mucositis, n=1; neutropenic fever, n=1), but there were no grade 4 events. The median dose intensity for capecitabine and mitomycin C was 100% during cycles 1 and 2 and only four patients required postponement of therapy. Of the 43 patients evaluable for efficacy, seven achieved partial and minor remissions (16%; 95% CI, 5-28%), and 12 patients (28%) had stable disease. The favourable safety profile and promising activity of the capecitabine/mitomycin C combination, even in heavily pretreated patients, warrant further evaluation in patients with advanced colorectal and gastric cancers.

Adult↗
PubMed2004

Fhit-deficient normal and cancer cells are mitomycin C and UVC resistant.

To identify functions of the fragile tumour suppressor gene, FHIT, matched pairs of Fhit-negative and -positive human cancer cell clones, and normal cell lines established from Fhit -/- and +/+ mice, were stressed and examined for differences in cell cycle kinetics and survival. A larger fraction of Fhit-negative human cancer cells and murine kidney cells survived treatment with mitomycin C or UVC light compared to matched Fhit-positive cells; approximately 10-fold more colonies of Fhit-deficient cells survived high UVC doses in clonigenic assays. The human cancer cells were synchronised in G1, released into S and treated with UVC or mitomycin C. At 18 h post mitomycin C treatment approximately 6-fold more Fhit-positive than -negative cells had died, and 18 h post UVC treatment 3.5-fold more Fhit-positive cells were dead. Similar results were obtained for the murine -/- cells. After low UVC doses, the rate of DNA synthesis in -/- cells decreased more rapidly and steeply than in +/+ cells, although the Atr-Chk1 pathway appeared intact in both cell types. UVC surviving Fhit -/- cells appear transformed and exhibit >5-fold increased mutation frequency. This increased mutation burden could explain the susceptibility of Fhit-deficient cells in vivo to malignant transformation.

Acid Anhydride Hydrolases↗
PubMed2006

Protection of the conjunctival flap from contact with mitomycin C during tunnel-trabeculectomy.

AIM: The mid-term appearance of the filtering bleb and surgical outcome following tunnel-trabeculectomy, in which protective measures were carried out to avoid contact between the mitomycin C (MMC) and the conjunctival flap, are presented. METHODS: In a retrospective study the records of 20 consecutive patients who had undergone tunnel-trabeculectomy >/=24 months earlier, using fornix-based conjunctival flap and MMC (0.4 mg/ml) application were evaluated. Inclusion criteria were patients in whom: (I) the MMC-socked sponge was applied without contact with the conjunctival flap; (II) during MMC washout, a second Weck cell sponge was held anterior to the conjunctival flap, to protect the flap from mitomycin contact during its back-flow. Excluded were five patients who either did not complete 24 months of follow-up (n=4) or underwent an intraocular surgery during that period (n=1). RESULTS: After 24-32 (26.9+/-2.2) months, the filtering bleb was completely vascularized and thick in 13/15 patients (86.7%), mostly vascularized with some para-limbal thick cysts in one and avascular and cystic in another. Mean intraocular pressure (IOP) dropped from a preoperative level of 25.3+/-7.0 mmHg with 3.5+/-0.9 hypotensive medications to 13.9+/-2.9 mmHg with 0.9+/-1.1 medications (P<0.0001, Wilcoxon test). Of the five excluded patients, the IOP ranged between 10 and 16 mmHg with 0-1 medications at the last examination, 1-15 months postoperatively. CONCLUSION: In this pilot study, an intraoperative protection of the conjunctival flap from mitomycin contact was mostly associated with a vascularized and thick filtering bleb after mid-term follow-up. Further controlled prospective studies are required to confirm these observations.

Adult↗
PubMed1995

Mitomycin C binding to poly[d(G-m5C)].

Poly[d(G-m5C)] was modified by reductively activated mitomycin C, an anti-tumour drug, under buffer conditions which are known to favour either the B or the Z conformations of DNA. C.d. and 31P-n.m.r. were used to characterize the poly[d(G-m5C)]-mitomycin cross-linked complexes, as well as the effects on the equilibrium between the B and Z forms of the polynucleotide. Mitomycin C appears to inhibit the B-->Z transition, even in the presence of 3 mM MgCl2, while the Z-form of poly[d(G-m5C)] does not interact significantly with the drug under bifunctionally activating conditions; thus no reversion from the Z-form to the B-form of the polynucleotide can be observed under the salt conditions which are required for the Z-form to exist.

Circular Dichroism↗
PubMed2003

Combined intravesical hyperthermia and mitomycin chemotherapy: a preliminary in vivo study.

Previous clinical studies of the combination of local intravesical hyperthermia with cytostatic drugs for the treatment of Superficial Transitional Cell Carcinoma of the urinary bladder (STCCB) showed encouraging results both in reducing recurrence rate to 20-30% within 2 years and in ablative success rate of 79%. Our objectives were to evaluate bladder tissue and adjacent organs during and following hyperthermia treatment. An intravesical catheter equipped with a radio-frequency antenna (Synergo SB-TS 101.1 System) was used for hyperthermia and intravesical chemotherapy (mitomycin C) was instilled in vivo for 60 min in two anaesthetized sheep. Thirteen to fifteen thermocouples were sewn surgically on the internal and external surfaces of the bladder wall and on adjacent organs to monitor the temperature during the treatment. We expected the intravesical temperature to be under 46 degrees C and the external layers below 45 degrees C. The bladder was filled with 50 mL of chemotherapeutic solution (400 micro g/mL of mitomycin C in distilled water). The sheep were sacrificed at the end of the treatment. Three other sheep, which underwent thoracic surgery, served as control group. Histological changes in both groups showed foci of oedema and haemorrhage with inflammation in the lamina propria and serosa. Foci of desquamation of the epithelium were noticed in the treated sheep. Histological analysis of the treated group showed no significant differences from the control group. The control group showed similar changes, some less pronounced. The combined treatment of hyperthermia with mitomycin C did not cause major damage to the urinary bladder or adjacent organs. All changes were superficial and reversible, and the control group showed similar changes, some less pronounced. Although this is an experimental model based on one single session treatment, rather than repeated treatments, it suggests that the approach may be useful in future studies both in models and man.

Adipose Tissue↗