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PubMed2005

Effect of mitomycin C on the secretion of granulocyte macrophages colonies stimulating factor and interleukin-5 in eosinophilic nasal polyps stromal culture.

UNLABELLED: The research involving tissue factors, such as granulocyte macrophage colonies stimulating factor (GM-CSF) and interleukin 5 (IL-5), leads to the mechanisms involved in the maintenance of eosinophilia, which is essential for the pathogenesis on eosinophilic nasal polyps. Mitomycin C has been successfully used in otolaryngology. AIM: The objective of this study was to evaluate the effect of mitomycin C in secretion of GM-CSF and IL-5 on eosinophilic nasal polyps. STUDY DESIGN: Case-control. MATERIAL AND METHOD: This is a comparative and auto-matched experimental study, performed with fragments of polyps which had been obtained from biopsy of patients with eosinophilic nasosinusal polyposis. The fragments of the experimental group were treated with mitomycin C (400 microg/ml) for 5 minutes and then washed in RPMI substrate. At time zero, 12 and 24 hours, the surface material was taken to determination of its GM-CSF levels in 22 patients and of IL-5 levels in 19 patients, by ELISA method. RESULTS: Reduction in GM-CSF expression on the experimental group at time 24 h (p< or = 0.05). The treated group presented significant GM-CSF expression between zero time and 12 h time (p= 0.013) showing the culture viability such as in the non-treated group. Tendency to decreasing IL-5 levels on the treated groups at 24 hours. CONCLUSION: This study showed that mitomycin C was efficient in inhibiting GM-CSF synthesis with reduction of IL-5 secretion, but this fact needs complementary studies.

Adolescent↗
PubMedDate not supplied

Properties of mitomycin C-albumin conjugates in vitro and in vivo.

Mitomycin C, an antineoplastic agent, was covalently attached to bovine serum albumin through a spacer of the glutaryl group. Two different synthetic methods were adopted; one was by the prior glutarylation of albumin followed by binding to mitomycin C, and the other was by the synthesis of glutarylated mitomycin C followed by binding to albumin. Physicochemical properties of the conjugates, such as Stokes radius, molecular weight, and helical content, were comparatively examined. The glutarylation of albumin resulted in an increase in Stokes radius of the protein due to the conformational change. The conjugates significantly stabilized mitomycin C and liberated it gradually under the physiological condition (t1/2 = 66-84 h). Both conjugates accumulated effectively in the tumor tissues. However, the distribution behavior of the conjugates depended on physicochemical properties such as molecular size. Treatment with the conjugates suppressed the tumor growth and increased the survival rate in the tumor-bearing mice.

Animals↗
PubMed1989

DNA sequence specificity of mitomycin cross-linking.

Using a gel electrophoresis assay, we show that the target DNA sequence cross-linked by N-methylmitomycin A, its aziridinomitosene, and mitomycin C is CpG, in strong preference over GpC. The yield per CpG site increases as the number of successive CpG sequences increases. Molecular modeling reveals no systematic difference between the energies of mitomycin cross-links at CpG in comparison with GpC. However, the distance between guanine amino groups in CpG sequences is nearly the same as the distance in the cross-linked adduct, whereas the amino group separation at GpC sites is substantially larger in the starting DNA than in the adduct. We suggest that the favorable placement of the second reaction center in CpG greatly accelerates the second step in the cross-linking reaction. As shown by a competition assay, mitomycins bind A-T and G-C sequences noncovalently equally well, even though the only sequence that yields appreciable cross-linking is CpG. N-Methylmitomycin A and its aziridinomitosene are found to be better cross-linking agents than is mitomycin C.

Base Sequence↗
PubMed1989

DNA cross-linking by intermediates in the mitomycin activation cascade.

We have assayed the cross-linking of oligonucleotides containing repeated mitomycin-reactive CpG sites in order to assess the factors that enhance activation of the carbamoyl function at C10, yielding efficient mitomycin cross-linking. Drugs studied include mitomycin C (MC), N-methylmitomycin A (NMA), and the aziridinomitosene of NMA (MS). Drugs were reduced both by catalytic hydrogenation and by diothionite. We find that cross-linking by fully reduced NMA can be increased severalfold by addition of either excess dithionite reductant or the oxidant FeCl3. Enhancement by FeCl3 is not seen with MC or MS, but excess dithionite increases cross-linking by all three compounds. We explain the action of Fe3+ by postulating production of the semiquinone of the monoadduct of mitomycin reacted at the C1-position; according to this mechanism, departure of the carbamate from C10 is more efficient for the semiquinone than for the hydroquinone. However, our results imply that the hydroquinone can also function as a cross-linking agent. Excess dithionite, beyond that required for stoichiometric reduction, activates the carbamate 2-3-fold for cross-linking. We find that the fully reduced leucoaziridinomitosene is highly unstable in solution, yet it produces efficient cross-liking. Hence, this compound is highly reactive in DNA alkylation and a good candidate for the role of primary alkylating agent.

Base Sequence↗
PubMed1989

New 2-substituted indoloquinone mitomycin analogues.

Previously reported 2-(hydroxymethyl)indoloquinones, prepared as their acetates or carbamates, were less active than 2-methyl analogues in bacterial cultures and they had no activity in mice, despite functionality appropriate for DNA cross-linking. On the basis of the hypothesis that these compounds might have been too reactive chemically for selective alkylation of DNA, we prepared new analogues with substituents that could give variation in the reduction potential of the quinone ring, which might control their rate of bioactivation. The 5-methoxyindoloquinones were much more potent cytotoxics than mitomycin C against human tumor cell lines, but they were inactive against P388 leukemia in mice. Two 5-aziridinylindoloquinones were also more potent than mitomycin C against the cell lines and one of them was active in the P388 model upon in vivo assay. The corresponding 5-amino analogues were less potent than mitomycin C against both the cell lines and murine P388 leukemia. A 2-(1-hydroxyethyl)carbamate was prepared by a 20-step synthesis. It was about one-fourth as potent as mitomycin C against two cell lines.

Antineoplastic Agents↗
PubMed2001

Toxic effects of subconjunctival 5-fluorouracil and mitomycin C on ciliary body of rats.

PURPOSE: The effects of subconjunctival injection of mitomycin C and different concentrations of 5-fluorouracil on the epithelium of the ciliary body of twenty Sprague Dawley SD rats was studied. METHODS: Twenty rats were divided into four treatment groups. The first three groups received 0.2 ml of 5, 10, and 30 mg of 5-fluorouracil subconjunctivally respectively, and the fourth group 0.2 ml of 0.4 mg/ml mitomycin C subconjunctivally. The right eye received 0.2 ml of the antimetabolite, while the left eye was injected with 0.2 ml of saline subconjunctivally, as a control. The eyes were examined histologically, in a masked fashion, by light and by transmission electron microscopy. In each treatment group, two eyes were examined after one week, and three eyes were examined one month after the subconjunctival injection. RESULTS: Electron microscopy revealed toxic effects in the epithelium of the ciliary body of all treatment groups. The 5-fluorouracil group revealed focal mitochondrial edema, enlargement of intercellular spaces, and dilatation of intracellular spaces. The mitomycin C group showed pyknotic nuclei, enlargement of intercellular spaces, and irregular flattened epithelial cells. The severity of changes correlated with concentration and length of exposure. No pathology was found by light microscopy in all groups. CONCLUSIONS: This study demonstrates that subconjunctival antimetabolites mitomycin C and 5-fluorouracil can penetrate the sclera and exert toxic effects on the epithelium of the ciliary body, even in low doses. These changes were only apparent by electron microscopy and were still present one month after the injection. These findings may contribute to the theory that the application of antimetabolites during or after surgery has a direct effect on the epithelium of the ciliary body, besides its known effect on the conjunctiva. Further studies are needed to evaluate its effect on intraocular pressure.

Animals↗
PubMed2003

Effects of thick Tenon's capsule on primary trabeculectomy with mitomycin-C.

PURPOSE: To investigate the effects of thick Tenon's capsule on primary trabeculectomy with adjunctive mitomycin-C. METHODS: In this prospective interventional case series of 45 consecutive uncomplicated glaucoma patients, 45 eyes with thick Tenon's capsule underwent primary trabeculectomy with intraoperative mitomycin-C (0.4 mg/ml for 3 min). Success was defined as intraocular pressure (IOP) <or= 21 mmHg with (qualified) or without (complete) medications. RESULTS: The mean follow-up period was 22.55 months. The mean preoperative IOP and number of medications were 28.91 +/- 7.06 mmHg and 1.68 +/- 0.73, respectively. The postoperative IOPs and the number of medications at all intervals were significantly lower than preoperative levels (p < 0.01 for each interval). The mean IOP was 11.03 +/- 3.93 mmHg (12.17 +/- 4.98 mmHg) at 24 months (12 months). Kaplan-Meier survival analysis revealed a qualified success rate of 93.1% (95.6%) after 24 months (12 months). During follow-up of the 45 eyes, 38 (84.4%) developed avascular thin-walled bleb, seven eyes (15.6%) had hypotony (IOP < 6 mmHg), 14 eyes (31.1%) had a shallow anterior chamber, and one eye (2.2%) had endophthalmitis. CONCLUSIONS: The use of mitomycin-C is associated with high success rates and good IOP control even in the presence of thick Tenon's capsule. However, thick Tenon's capsule does not seem to eliminate the development of complications in eyes undergoing primary trabeculectomy with mitomycin-C.

Adult↗
PubMed2001

Equivalent efficacy of mitomycin C plus doxorubicin instillation to bacillus Calmette-Guerin therapy for carcinoma in situ of the bladder.

BACKGROUND: To elucidate the most efficient topical therapy for carcinoma in situ of the bladder, the efficacy of intravesical mitomycin C plus doxorubicin therapy was compared with bacillus Calmette-Guerin (BCG) therapy. The clinical behavior of the tumor was analysed according to the histological grade. METHODS: Forty-two patients with carcinoma in situ of the bladder were randomized to intravesical BCG (21 patients) or mitomycin C plus doxorubicin sequential therapy (21 patients) as first line treatment. The non-responders underwent the subsequent instillation of the other intravesical therapy alternately. Of the patients, 27 had grade 2 and 15 had grade 3 cancer. RESULTS: Both topical therapies were equally effective with initial response rates of 86% (18/21) for BCG and 81% (17/21) for mitomycin C plus doxorubicin, irrespective of the tumor grade. Of seven initial non-responders, five patients achieved a complete response by subsequent instillation, resulting in a total response rate of 95%. After a mean follow-up of 47 months, five patients (12%) developed disease progression. The progression rates were not different between the topical therapies, but were significantly higher in grade 3 than in grade 2 cases. CONCLUSION: It appears likely that mitomycin C plus doxorubicin instillation has an equivalent efficacy to BCG as the initial therapy of carcinoma in situ and the combination of them would be the most efficient treatment for the disease. Moreover, histological grading would be clinically useful in defining the tumor characteristics and behavior of carcinoma in situ of the bladder.

Adjuvants, Immunologic↗
PubMed2001

[The treatment of a primary acquired melanosis of the conjunctiva with atypia by low dose of Mitomycin C 0.02 % - case report with follow up of 2 years].

BACKGROUND: About 70 % of the melanomas of the conjunctiva develop from an primary acquired melanosis (PAM) with atypia. This is the reason why excision, radiation, cryotherapy or a combination of them are proposed for therapy. But, if the acquired melanosis is very large, serious complications will be found with that treatment. PATIENT AND METHOD: A 65-year-old woman has shown a large melanosis of the conjunctiva of her left eye. Biopsies, taken from different sites of the conjunctiva, have confirmed the diagnosis of an acquired melanosis of the conjunctiva with atypia. This has been the reason for our Mitomycin C 0.02 % therapy for one week. It has been repeated once again after half a year. RESULTS: Atypia of the cells was shown in the upper cell layer of the conjunctiva after the first therapy. But after the second therapy no atypia of the cells was present within two years after the last treatment, examining several biopses. CONCLUSION: Looking for an effective treatment without complications, a new therapy with Mitomycin C has been introduced in the last years. As it is not yet clearly known how to use Mitomycin to have maximal effectiveness with minimal complications, the reports about doses and frequency are differing a lot in the literature and are more often considerably lying over the introduced effective dose of our case. If Mitomycin is used in that low dosage and in that special application as shown, it could be a very efficient therapy with less complications.

Administration, Topical↗
PubMed1995

[Follow-up of a pilot study of trabeculectomy with low dosage mitomycin C (0.2 mg/ml for 1 minute). Independent evaluation of a retrospective nonrandomized study].

BACKGROUND: The application of anti fibroses agents during glaucoma surgery leads to more satisfactory results with lower i.o. pressure, yet eliciting complications in wound healing, avascular filtering blebs and frequent chronic hypotonias. In patients with lower risk for failure a reduction of concentration and application time of Mitomycin C should minimise side effects while maintaining the beneficial effect of lower intraocular pressure. PATIENTS AND METHODS: 34 eyes of 32 patients (age 72 +/- 8) underwent trabeculectomy (14 combined with phacoemulsification and implantation of a foldable posterior chamber lens). During filtering surgery, Mitomycin C (0.2 mg/ml for 1 min) was applied after preparation of the scleral flap. An 11.5 +/- 5.0 (3-21), month followup, 30 (34) eyes (88.2%) had an i.o. pressure of < or = 21 mm Hg (14.0 +/- 4.3 mm Hg at the last control) without additional glaucoma medications. RESULTS: The majority of filtering blebs (30/34; 88.2%) were well vascularised, often showing polycystic degenerations near the limbus. Only 3 eyes developed an avascular filtering bleb. No persisting leaks were observed and only 2 of 34 eyes (5.9%) developed short transient hypotonia (IOP < 6 mm Hg). CONCLUSIONS: Adjunctive treatment with low concentration of Mitomycin C during filtering surgery results in good i.o. pressure with little risk of avascular bleb development. A prospective, randomised trial is required to assess the safety and efficacy of adjuvantive Mitomycin C treatment in low risk filtering surgery.

Aged↗
PubMed1982

[Microangiopathic haemolytic anaemia as a complication of mitomycin C treatment (author's transl)].

Microangiopathic haemolytic anaemia developed in 5 (out of 14) patients treated with mitomycin C combinations, having received 4 or more treatment cycles. This finding necessitates restricted use of broad and longterm use of mitomycin C, particularly in view of the occasionally fatal outcome of this toxic complication. Adjuvant treatment with mitomycin C does not appear acceptable any longer. Patients treated with mitomycin C should be monitored carefully for occurrence of schistocytosis and platelet deficiency as very early signs of microangiopathic haemolytic anaemia.

Adult↗
PubMed1974

Sister chromatid exchanges, indices of human chromosome damage and repair: detection by fluorescence and induction by mitomycin C.

Sister chromatid exchanges in chromosomes from human lymphocytes grown two replication cycles in medium containing 5-bromodeoxyuridine can be detected by fluorescence microscopy after staining with the bisbenzimidazole dye 33258 Hoechst. These exchanges are much more frequent than chromosome or chromatid breaks and appear to be partly but not entirely due to 5-bromodeoxyuridine incorporation. Sister chromatid exchanges are extremely sensitive indicators of chromosome damage produced by DNA cross-linking agents such as mitomycin C. Significant increases in the sister chromatid exchange frequency occur with 3 ng/ml of mitomycin C; higher concentrations of mitomycin C induce further sister chromatid exchanges. Comparatively few gross chromosomal aberrations are seen in cells exhibiting as many as one hundred or more sister chromatid exchanges. Most of the damage caused by mitomycin C to chromosomal DNA is apparently repaired without detectable changes in chromosome morphology. Analysis of sister chromatid exchanges may permit more sensitive detection of damage to DNA caused by other agents than has previously been possible by classical cytological techniques.

Benzimidazoles↗
PubMed1983

Lack of Z-DNA conformation in mitomycin-modified polynucleotides having inverted circular dichroism.

Poly(dG-dC) . poly(dG-dC) and Micrococcus lysodeikticus DNA were modified by exposure to reductively activated mitomycin C, an antitumor antibiotic. The resulting covalent drug-polynucleotide complexes displayed varying degrees of CD inversions, which are strikingly similar to the inverted spectrum observed with Z-DNA. The following criteria have been used to establish, however, that the inverted CD pattern seen in mitomycin C-polynucleotide complexes does not reflect a Z-DNA conformation. (i) The ethanol-induced transition of poly(dG-dC) . poly(dG-dC) from B to Z conformation is not facilitated but rather is inhibited by mitomycin C modification. This may be due to the presence of crosslinks, (ii) Radioimmunoassay indicated no competition for Z-DNA-specific antibody by any of the mitomycin C-modified polynucleotides, (iii) 31P NMR of the complexes yielded a single relatively narrow resonance, which is inconsistent with the dinucleotide repeat characteristic of Z-DNA. Alternative explanations for the inverted CD pattern include a drug-induced left-handed but non-Z conformational change or the superposition of an induced CD onto the CD of B-DNA due to drug-base electronic interactions. These results illustrate the need for caution in interpreting CD changes alone as an indication of Z-DNA conformation.

Circular Dichroism↗
PubMed2004

A phase II study of UFT and Leucovorin in combination with mitomycin C in patients with metastatic colorectal cancer.

The main objectives of this phase II study were to determine efficacy and safety of the combination of UFT with Leucovorin and mitomycin C in patients with metastatic colorectal cancer. Ninety-seven patients were treated with UFT (91 patients 300 mg/m2, 6 patients 250 mg/m2) + Leucovorin 90 mg days 1-28 q 5 weeks. During the first 4 cycles the patients also received mitomycin C 7 mg/m2 on day 1. At the end of 4 courses patients with benefit from the treatment could receive further courses of UFT and Leucovorin alone. Two patients had a complete response (2%), 20 (21%) had a partial response, 40 (41%) had no change, 19 (20%) had progression, and 16 (17%) were not evaluable for response. The overall response rate by intention to treat was 22/97 (23%). Median time to progression was 5 months and median survival 13 months. Severe (grade 3-4) toxicities included: anorexia 3%, nausea 6%, vomiting 7%, diarrhoea 7%, and fatigue 9%. Febrile neutropenia, renal failure, and thrombocytopenia were seen in 1% of the patients, respectively. The combination of UFT with Leucovorin and mitomycin C shows similar clinical activity with regard to overall response rate (23%) and survival (13 months) to other frontline 5-fluorouracil-based therapies in metastatic colorectal cancer patients. The results indicate that mitomycin C did not increase either efficacy or toxicity. Therefore, phase III trials with this regimen cannot be recommended.

Adult↗
PubMed2000

Effects of intraperitoneal mitomycin C adsorbed on activated carbon on adhesion formation and mesothelial cells in vitro.

OBJECTIVE: To investigate the incidence of adhesions after intraperitoneal instillation of mitomycin C adsorbed on activated carbon (MMC-CH). DESIGN: Animal and laboratory studies. SETTING: University hospital, Germany. ANIMALS: 90 Sprague-Dawley rats. INTERVENTIONS: Laparotomy, small bowel anastomosis, and intraperitoneal instillation of saline (controls, n = 27), activated carbon alone (n = 24) or MMC-CH (n = 26). Cultures of monolayers of human mesothelial cells. MAIN OUTCOME MEASURES: Measurements of adhesions by planimetry. Toxicity of mitomycin C alone and charcoal alone in mesothelial cell monolayers as reflected by cell proliferation and measurement of lactate dehydrogenase activity. Concentrations of plasminogen activator (tPA) and plasminogen activator inhibitor 1 (PAI-1) as measures of the fibrinolytic activity of mesothelial cells. RESULTS: Both activated carbon and MMC-CH caused a significant increase of adhesion formation in rats. Activated carbon also reduced the fibrinolytic activity of mesothelial cells, and mitomycin C caused concentration-dependent cytotoxicity in vitro. CONCLUSIONS: Activated carbon combined with high concentrations of mitomycin C may cause intraperitoneal infective complications by increasing the rate of adhesion formation and reducing the fibrinolytic activity of mesothelial cells. We recommend a new absorbable carrier for intraperitoneal chemotherapy.

Animals↗
PubMed1991

The effects of topical mitomycin on glaucoma filtration surgery in rabbits.

A prospective, randomized, double-masked, and placebo controlled study was performed to examine the effects of topically applied mitomycin on the success of full thickness filtration surgery in 23 rabbits. Both eyes of each rabbit had surgery by the same surgeon. After surgery, the experimental eye received a single subconjunctival injection of mitomycin (0.2 mg), and 50 microliters of a 0.2 mg/cc solution of mitomycin topically four time daily. The fellow control eyes were treated with sterile water. The mean intraocular pressure reduction from baseline exhibited by the experimental eyes was greater than that observed for the control eyes. The difference in intraocular pressure reduction between the two groups was statistically significant from post-operative day three through day 21 (p less than .05). With survival analysis, fewer failures were noted in the experimental eyes compared to control eyes for each time period throughout the study (p less than .005). The experimental eyes also demonstrated a longer time to bleb failure although this difference did not achieve statistical significance (p less than .10). An additional five rabbits were treated with the experimental drop in one eye and sterile water in the fellow eye but underwent no surgery. No differences between eyes were noted with regard to intraocular pressure change or anterior segment pathology. These data demonstrated the efficacy of mitomycin in promoting filtration surgical success in rabbits.

Administration, Topical↗
PubMed1992

THC:YAG laser sclerostomy with mitomycin subconjunctival injection in rabbits.

We performed sclerostomy using THC:YAG laser (thulium, holmium, chromium doped YAG crystal) and subconjunctival injection of mitomycin soon after the filtering process in rabbits to observe the lowering effect of intraocular pressure(IOP) and filtering bleb formation. A 1-mm conjunctiva wound was made 12 mm away from the sclerostomy site to allow the entry of the optic probe for delivering energy. Forty-eight rabbits were divided into 3 groups. After sclerostomy, Group I received 0.2 ml normal saline subconjunctival injection and Group II and III received 0.2 ml mitomycin injection of 0.1 and 0.2 mg/ml respectively. One eye of each rabbit was randomly selected for the experiment while the fellow eye served as control. The bleb lasted 1.4 +/- 0.5 days (or 1 to 2 days) in Group I, 8.5 +/- 4.5 days (or 4 to 17 days) in Group II and 15.4 +/- 10.9 days (or 4 to 37 days) in Group III. The IOP lowering effect was significantly enhanced in Group III. The postoperative complication was minimal corneal punctate erosion in the mitomycin group, but all of them, however, resolved within one week. The results demonstrated that mitomycin is effective in prolonging the filtering effect produced by the THC:YAG laser.

Animals↗
PubMed1997

Mitomycin-C induced hemolytic uremic syndrome: a case report and literature review.

Hemolytic uremic syndrome spontaneously arises in a few patients with advanced cancer, but it is more commonly related to the use of certain chemotherapeutic agents. Mitomycin-C is, etiologically, the most common causative agent inducing hemolytic uremic syndrome, in a dose dependent manner. We report this syndrome, attributable to mitomycin-C at a cumulative dose of 40 mg/m2, in a gastric cancer patient. A 42-year-old female with stage III gastric cancer underwent radical gastrectomy and was given mitomycin-C at 10 mg/m2 intravenously every four weeks as adjuvant therapy. Hemolytic uremic syndrome was diagnosed three months after the last dose of mitomycin-C administration. The most prominent symptoms included pallor, hypertension and anasarca, with laboratory evidence of microangiopathic hemolytic anemia, azotemia and hyperkalemia. Her disease was progressive, but fortunately stabilized after staphylococcus column A dialysis. Her disease remained in remission for 24 months from the time of diagnosis, and then relapsed in the form of peritoneal carcinomatosis with partial intestinal obstruction.

Adenocarcinoma↗