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PubMed1999

Subconjunctival mitomycin C for the treatment of ocular cicatricial pemphigoid.

PURPOSE: The authors performed a prospective evaluation of the efficacy of treating ocular cicatricial pemphigoid (OCP) with subconjunctival mitomycin C. DESIGN: Unmasked, prospective, internally controlled case series. METHODS: Patients were eligible for treatment with subconjunctival mitomycin C under three criteria: (1) significant complications of systemic immunosuppressant therapy; (2) markedly asymmetric conjunctival disease; and (3) end-stage OCP. All patients received monocular subconjunctival injections of 0.25 ml of 0.2 mg/ml mitomycin C to both the superior and inferior bulbar conjunctivae in the eye with the more severe disease. RESULTS: Nine eyes of nine patients (mean age, 74 years) were treated with subconjunctival mitomycin C to the more-involved eye and were followed for a mean of 23.5 months (range, 12-40 months). Eight of nine patients showed quiescence of their OCP in the treated eye based on serial evaluation of conjunctival cicatrization and grading of conjunctival erythema. Five of the nine untreated eyes showed progression of the conjunctival disease. One patient required concomitant systemic immunosuppressive therapy after subconjunctival mitomycin C. Two patients underwent successful visual rehabilitative surgery in the mitomycin C-treated eye. CONCLUSION: The use of subconjunctival mitomycin C may be effective in preventing progression of conjunctival cicatrization and erythema in patients with OCP. No complications of mitomycin C treatment were noted. Long-term follow-up and further investigation into the efficacy of subconjunctival mitomycin C in the management of OCP is warranted.

Aged↗
PubMed1990

NMR and computational characterization of mitomycin cross-linked to adjacent deoxyguanosines in the minor groove of the d(T-A-C-G-T-A).d(T-A-C-G-T-A) duplex.

Two-dimensional homonuclear and heteronuclear NMR and minimized potential energy calculations have been combined to define the structure of the antitumor agent mitomycin C (MC) cross-linked to deoxyguanosines on adjacent base pairs in the d(T1-A2-C3-G4-T5-A6).d(T7-A8-C9-G10-T11-A12) duplex. The majority of the mitomycin and nucleic acid protons in the MC-X 6-mer complex have been assigned from through-bond and through-space two-dimensional proton NMR studies in aqueous solution at 5 and 20 degrees C. The C3.G10 and G4.C9 base pairs are intact at the cross-link site and stack on each other in the complex. The amino protons of G4 and G10 resonate at 9.36 and 8.87 ppm and exhibit slow exchange with solvent H2O. The NMR experimental data establish that the mitomycin is cross-linked to the DNA through the amino groups of G4 and G10 and is positioned in the minor groove. The conformation of the cross-link site is defined by a set of NOEs between the mitomycin H1" and H2" protons and the nucleic acid imino and amino protons of G4 and the H2 proton of A8 and another set of NOEs between the mitomycin geminal H10" protons and the nucleic acid imino and amino protons of G10 and the H2 proton of A2. Several phosphorus resonances of the d(T-A-C-G-T-A) duplex shift dramatically on mitomycin cross-link formation and have been assigned from proton-detected phosphorus-proton two-dimensional correlation experiments. The proton chemical shifts and NOEs establish fraying at the ends of the d(T-A-C-G-T-A) duplex, and this feature is retained on mitomycin cross-link formation. The base-base and base-sugar NOEs exhibit similar patterns for symmetry-related steps on the two nucleic acid strands in the MC-X 6-mer complex, while the proton and phosphorus chemical shifts are dramatically perturbed at the G10-T11 step on cross-link formation. The NMR distance constraints have been included in minimized potential energy computations on the MC-X 6-mer complex. These computations were undertaken with the nonplanar five-membered ring of mitomycin in each of two pucker orientations. The resulting low-energy structures MX1 and MX2 have the mitomycin cross-linked in a widened minor groove with the chromophore ring system in the vicinity of the G10-T11 step on one of the two strands in the duplex.(ABSTRACT TRUNCATED AT 400 WORDS)

Base Sequence↗
PubMed2001

Synthesis, DNA cross-linking activity, and cytotoxicity of dimeric mitomycins.

Dimeric DNA cross-linking compounds have emerged as important new antitumor agents. We report the synthesis and biochemical evaluation of a select set of dimeric mitomycins in which the two mitomycin units are tethered at either the mitomycin C(7) amino or the aziridine N(1a) positions. Significantly, mitomycin C (1) itself is the prototypical bioreductive DNA cross-linking agent. DNA cross-linking experiments using a denaturing-gel-electrophoresis-based assay showed that the extent of DNA cross-linking for select dimeric mitomycins can exceed that of the parent compound, mitomycin C, and that the reaction proceeds, in part, at the two distal C(1) sites in the mitomycins. The efficiency of DNA cross-linking depended on the nature of the linker and the position of linker unit's attachment. When we compared the efficiency of DNA cross-linking for the dimeric mitomycins with their in vitro cytotoxicities in cultured human tumor cells, we observed a poor correlation. The mitomycins that gave the highest levels of DNA cross-linked adducts displayed the weakest cytotoxicities. These findings determined that the denaturing-gel-electrophoresis-based assay was a poor predictor of cytotoxic activity.

Antibiotics, Antineoplastic↗
PubMed1994

Filtering surgery with mitomycin-C in uncomplicated (primary open angle) glaucoma.

Mitomycin is an antibiotic with antineoplastic activity which inhibits fibroblast proliferation in the operative field in glaucoma filtering surgery. The authors retrospectively evaluated the effectiveness of trabeculectomy with mitomycin-C as an initial surgical procedure in uncomplicated (primary open angle) glaucoma in 17 eyes of 17 patients; 12 eyes of 12 patients that received standard trabeculectomy constituted the control group. Mitomycin was applied at a concentration of 0.5 mg/ml for 3 min to the episclera and 2 min under the scleral flap. Median values for preoperative intraocular pressure was 43 mmHg (range 26-65) in the control group and 40 mmHg (range 30-60) in the mitomycin group (p > 0.05, Mann-Whitney U-test). After an average follow-up of 17 months, median postoperative IOP was 10 mmHg (range 3-18) in the control group and 4 mmHg (range 1.1-20) in the mitomycin group (p < 0.05, Mann-Whitney U-test). Percentage IOP drop was 75.6% in the control group (range 30.8-93.5%) and 89.6% (range 54.2-98%) in the mitomycin group (p < 0.05, Mann-Whitney U-test). The postoperative visual acuities of the two groups did not differ significantly (p > 0.05, Fisher exact test). Although there was not a statistically significant difference between complications, such as elevated intraocular pressure, wound leakage or bleb ulceration in both groups (p > 0.05, Fisher exact test), the number of hypotonous eyes (having an average IOP < or = 5 mmHg) was significantly higher in the mitomycin-C group compared to the controls (p < 0.05, Fisher exact test). Mitomycin established a well formed bleb and reduced the IOP more effectively than did the standard filtering procedure (p < 0.05, Mann-Whitney U-test); however, further work is necessary to evaluate the long-term complications of mitomycin-C surgery such as hypotony. This would help clear any doubts about the safety of this procedure on long-term.

Adult↗
PubMed2000

Results of intraoperative mitomycin C application in dacryocystorhinostomy.

AIMS: To evaluate the long term results of intraoperative mitomycin C application in dacryocystorhinostomy (DCR) surgery compared with results of the conventional procedure. METHODS: In this prospective randomised controlled study, a total of 88 eyes diagnosed with acquired nasolacrimal duct obstruction were randomly divided into a conventional DCR group and a mitomycin C group in which mitomycin C was used during DCR surgery. The surgical procedures in both groups were exactly the same, except that in the patients in the mitomycin C group, a piece of neurosurgical cottonoid soaked with 0.2 mg/ml mitomycin C was applied to the osteotomy site for 30 minutes. The results of the DCR surgeries were evaluated by objective findings such as irrigation and the height of tear meniscus and subjective symptoms by asking patients the condition of tearing improvement. RESULTS: Among the 44 eyes in the mitomycin C group, 95.5% of patients remained totally symptom free after 10 months of follow up; while in the conventional group, 70.5% of patients were reported to be symptom free and 18% of patients to have an improvement in their symptoms. There was a significant difference between these two groups. As far as objective findings were concerned, there were 41 eyes in the mitomycin C group classified as having a normal and one eye with moderate tear meniscus level, compared with 32 eyes and seven eyes, respectively, in the conventional group. There was also a significant difference between these two groups. The non-patency rate in the mitomycin C group is 4.5% compared with 11.4% in the conventional group. There were no complications such as abnormal nasal bleeding, mucosal necrosis, or infection except one patient with delayed wound healing. CONCLUSIONS: Intraoperative mitomycin C application is effective in increasing the success rate of DCR surgery in standard nasolacrimal duct obstruction, and no significant complications resulted from its use.

Dacryocystorhinostomy↗
PubMed2005

Mitomycin-C induces the apoptosis of human Tenon's capsule fibroblast by activation of c-Jun N-terminal kinase 1 and caspase-3 protease.

PURPOSE: To investigate whether mitochondrial dysfunction and mitogen-activated protein kinase family proteins are implicated in apoptotic signaling of human Tenon's capsule fibroblasts (HTCFs) by mitomycin-C. METHODS: Apoptosis was determined by Hoechst nuclei staining, agarose gel electrophoresis, and flow cytometry in HTCFs treated with 0.4 mg/mL mitomycin-C for 5 minutes. Enzymatic digestion of florigenic biosubstrate assessed the catalytic activity of caspase proteases, including caspase-3, caspase-8, and caspase-9. Phosphotransferase activity of c-Jun N-terminal kinase (JNK) 1 was measured by in vitro immune complex kinase assay using c-Jun(1-79) protein as a substrate. Mitochondrial membrane potential transition (MPT) was measured by flow cytometric analysis of JC-1 staining. RESULTS: Mitomycin-C (0.4 mg/mL) induced the apoptosis of HTCFs, which was characterized as nucleic acid and genomic DNA fragmentation, chromatin condensation, and sub-G(0)/G(1) fraction of cell cycle increase. The catalytic activity of caspase-3 and caspase-9 was significantly increased and was accompanied by cytosolic release of cytochrome c and MPT in response to mitomycin-C. Treatment with mitomycin-C resulted in the increased expression of Fas, FasL, Bad, and phosphorylated p53 and a decreased level of phosphorylated AKT. Treatment with mitomycin-C also increased the phosphotransferase activity and tyrosine phosphorylation of JNK1, whose inhibitor significantly suppressed the cytotoxicity of mitomycin-C. CONCLUSIONS: Mitomycin-C induced the apoptosis of HTCFs through the activation of intrinsic and extrinsic caspase cascades with mitochondrial dysfunction. It also activated Fas-mediated apoptotic signaling of fibroblasts. Furthermore, the activation of JNK1 played a major role in the cytotoxicity of mitomycin-C.

Antibiotics, Antineoplastic↗
PubMed1999

A dose-escalation phase II clinical trial of infusional mitomycin C for 7 days in patients with advanced measurable colorectal cancer refractory or resistant to 5-fluorouracil.

Chemotherapy for 5-fluorouracil (5-FU)-resistant colorectal cancer is largely ineffective with new and innovative therapeutic strategies needed to benefit patients developing progressive disease while receiving 5-FU or 5-FU-based programs. The tumor antibiotic mitomycin C is an alkylating agent with a broad range of clinical activity in a variety of gastrointestinal malignancies and is therefore a reasonable agent to test for clinical activity in the setting of 5-FU-resistant or -refractory colorectal cancer. The principal goal of this study is to investigate the logistical feasibility and clinical efficacy of a 7-day infusion of mitomycin C, delivering an equitoxic dose to the standard bolus delivery in patients with progressive disease while receiving 5-FU-based chemotherapy. Twenty-five patients with advanced measurable colorectal cancer, resistant or refractory to 5-FU-based chemotherapy, were treated with a 7-day intravenous infusion of mitomycin C. Doses ranged between 1.5 and 3.0 mg/M2/day for total cumulative mitomycin C, ranging between 10.5 and 21.0 mg/M2 per chemotherapy cycle. Forty-four courses of infusional mitomycin C were delivered to 25 patients via surgically implanted venous access devices. The median age of all patients was 63 years (range, 27-83); there were 11 men and 14 women. Eleven patients had received two or more prior chemotherapy combinations, with the average number of prior therapies before mitomycin C being 1.6. The median number of cycles of mitomycin C administered was two (range, one to six). Thirty-seven of 44 cycles were administered at the dose range of 2.0-3.0 mg/M2/day. Hematologic toxicity was mild, with only three courses associated with grade III thrombocytopenia and one course with grade III neutropenia. No extrahematologic toxicities were observed. No patient had a complete response; two patients (8%) showed partial responses that lasted for 145 and 190 days. One patient had stable disease for 180 days. Twenty-two of 25 patients (88%) developed progressive disease during mitomycin C administration. Infusional mitomycin C for 7 days, cycled every 42 days, is logistically feasible and associated with minimal clinical toxicity. Used on this schedule and with these doses in 5-FU-resistant/refractory colorectal cancer, however, there is no meaningful clinical activity for this agent, and it cannot be recommended as a salvage or second-line therapy in the treatment of metastatic colorectal cancer.

Adult↗
PubMed2006

Effect of prophylactic and therapeutic mitomycin C on corneal apoptosis, cellular proliferation, haze, and long-term keratocyte density in rabbits.

PURPOSE: To determine the mechanism through which topical mitomycin C prevents and treats corneal haze after photorefractive keratectomy (PRK) and to examine the effects of dosage and duration of exposure. METHODS: In 224 New Zealand rabbits, -9.0 diopter PRK with mitomycin C or balanced salt solution was performed. Haze level was graded at the slit-lamp. Rabbits were sacrificed at 4 hours, 24 hours, 4 weeks, or 6 months after surgery and immunohistochemistry was performed with TUNEL assay, Ki67, and alpha-SMA. RESULTS: TUNEL-positive apoptotic cells marginally increased in all mitomycin C groups whereas Ki67-positive mitotic cells decreased significantly following mitomycin C application. A greater decrease in myofibroblasts was noted with prophylactic mitomycin C treatment than therapeutic mitomycin C treatment. There was, however, an anterior stromal acellular zone (approximately 20% of the total stroma) in eyes treated with mitomycin C, which persisted to the maximum follow-up of 6 months. CONCLUSIONS: Mitomycin C treatment induces apoptosis of keratocytes and myofibroblasts, but the predominate effect in inhibiting or treating haze appears to be at the level of blocked replication of keratocytes or other progenitor cells of myofibroblasts. Treatment with 0.002% mitomycin C for 12 seconds to 1 minute appears to be just as effective as higher concentrations for longer duration in the rabbit model. However, a persistent decrease in keratocyte density in the anterior stroma could be a warning sign for future complications and treatment should be reserved for patients with significant risk of developing haze after PRK.

Animals↗
PubMed1999

Effectiveness of a single immediate mitomycin C instillation in patients with low risk superficial bladder cancer: short and long-term followup.

PURPOSE: We analyze the impact of a single mitomycin C instillation in patients with low risk superficial bladder cancer with short and long-term followup. MATERIALS AND METHODS: A total of 131 patients with low risk superficial bladder cancer were included in a prospective randomized controlled trial. All patients had a 3 cm or less single, papillary, primary or recurrent tumor and were disease-free for more than 1 year. Patients with muscular invasion, G3 tumor or bladder carcinoma in situ on pathological examination were excluded from study. The tumor was completely resected before patients were randomized into 2 arms of no further treatment (control group) and a single immediate instillation of 30 mg mitomycin C (mitomycin C group). Recurrences were considered early within the first 2 years of followup. RESULTS: At 24-month followup the recurrence-free interval was significantly increased, and recurrence, and recurrence and tumor per year rates were decreased in the mitomycin C compared to the control group. However, at long-term followup these differences were not statistically significant and the recurrence-free interval curves were parallel. A shorter hospital stay and catheterization period were noted in the mitomycin C group compared to the control group, which were not significant. Early recurrences were concentrated in the first year in the control but not in the mitomycin C group. A significant relationship between early and late recurrences was found in the mitomycin C but not in the control group. CONCLUSIONS: Our analysis confirms the positive effect of a single immediate mitomycin C instillation in patients with low risk superficial bladder cancer. This benefit is limited to early recurrence and is not maintained with long-term followup. Thus, this approach is an alternative to observation or endovesical chemotherapy. Our study also suggests that cell implantation as a mechanism of early recurrence can be controlled with a single mitomycin C instillation.

Administration, Intravesical↗
PubMed2000

Topical mitomycin chemotherapy for conjunctival malignant melanoma and primary acquired melanosis with atypia: clinical experience with histopathologic observations.

OBJECTIVES: To clinically evaluate topical mitomycin chemotherapy in patients with diffuse, multifocal, or recurrent primary acquired melanosis with atypia and/or conjunctival malignant melanoma and to histopathologically study ocular tissue samples obtained before and after treatment. METHODS: Chemotherapy with topical mitomycin, 0.04% 4 times daily, was administered for 28 days as the primary and only treatment in 7 patients (after biopsy) and for 7 days as adjuvant therapy to excision and cryotherapy in 5 patients. Mean follow-up was 38 months. Five patients developed subconjunctival recurrences, for which 2 underwent orbital exenteration and 3 were treated conservatively. Histopathologic specimens of conjunctival, adnexal, and ocular tissues obtained before and after chemotherapy were evaluated. RESULTS: Regression of tumor was observed in 11 patients with primary or adjuvant topical mitomycin chemotherapy. One patient with nodular melanoma was resistant to mitomycin chemotherapy. Histopathologic findings included regionally variable conjunctival epithelial atrophy and thinning. Dyskeratosis and focal keratinization in conjunctival epithelium were noted. Epithelial nuclei were occasionally pyknotic in areas of atrophic epithelium. Subepithelial inflammation was present and was most intense in areas with severe atrophy and/or keratosis. Two patients with primary treatment and 2 with adjuvant treatment developed subconjunctival recurrence. In patients with recurrent malignant melanoma, the deeper layers of the lamina propria were involved, with sparing of the epithelium and superficial lamina propria. Transient keratoconjunctivitis was observed in all patients during treatment. In evaluation of the exenteration specimens, corneal, scleral, episcleral, retinal, and anterior structures were within normal limits. CONCLUSIONS: Topical mitomycin chemotherapy was found to induce regression of conjunctival melanoma and primary acquired melanosis with atypia. When mitomycin chemotherapy was used as an adjuvant to excision and cryotherapy, 2 (40%) of 5 patients experienced tumor recurrence at a mean of 4.3 years' follow-up. Our histopathologic findings demonstrated a long-term mitomycin chemotherapy-related effect on the conjunctiva. The degree of chronic atrophy and inflammation was not clinically significant. The pattern of effect and location of recurrent disease suggest that this regimen of topical mitomycin chemotherapy was most effective for superficial tumors. No complications that would preclude use of our dose regimen were noted. Although subconjunctival or orbital recurrences were noted, topical mitomycin chemotherapy warrants further investigation as an alternative treatment for primary acquired melanosis with atypia and conjunctival malignant melanoma. Arch Ophthalmol. 2000;118:885-891

Administration, Topical↗
PubMedDate not supplied

Low-dose intraoperative mitomycin-C versus conjunctival autograft in primary pterygium surgery: long term follow-up.

PURPOSE: To evaluate and compare the long term safety and efficacy of low-dose intraoperative application of mitomycin-C (0.02%) with conjunctival autograft in primary pterygium surgery. PATIENTS AND METHODS: Of 37 consecutive patients 41 eyes with primary pterygium underwent pterygium excision with either intraoperative mitomycin-C (0.02%) (Group I) or conjunctival autografts (Group II) at random. Mitomycin-C (0.2 mg/mL) was applied for 2.5 minutes on the scleral bed under the conjunctiva. Conjunctival autograft was obtained from upper temporal limbus and secured with 10-0 monofilament nylon. The follow-up period ranged from 14 to 54 months (mean 36 months) for mitomycin-C group and 13 to 58 months (mean 38 months) for conjunctival autograft group. RESULTS: Twenty-one eyes underwent pterygium excision with intraoperative mitomycin-C (0.02%) application (Group I) and 20 eyes were treated using conjunctival autograft (Group II). The mean size of the pterygium was 3.80 mm (range 2.6 to 4.8 mm) in the mitomycin-C group and 3.60 mm (range 2.5 to 4.5 mm) in the conjunctival autograft group. Two (9.52%) eyes treated with intraoperative mitomycin-C had delayed epithelial healing of corneoscleral wound and one (4.76%) eye developed pyogenic granuloma. Three (14.3%) of the 21 eyes in Group I and one (5%) of 20 eyes in Group II had recurrence of pterygium (P = 0.3174). All recurrences occurred in patients below 40 years of age (P = 0.0384). CONCLUSION: We conclude that conjunctival autograft and intraoperative mitomycin-C are both equally effective adjuncts to primary pterygium surgery on long term follow-up. However, future prospective studies with larger numbers of subjects may be carried out to find out the optimum concentration and duration of intraoperative mitomycin-C application.

Adult↗
PubMed2002

Apoptosis gene expression and death receptor signaling in mitomycin-C-treated human tenon capsule fibroblasts.

PURPOSE: To examine the effect of mitomycin-C on the expression of apoptosis genes in human Tenon capsule fibroblasts and to evaluate whether death receptor signaling modulates mitomycin-C cytotoxicity. METHODS: Bcl-2, Bax, Bcl-x, Fas (CD95) and tumor necrosis factor (TNF) receptor expression was determined by flow cytometry in control and mitomycin-C-treated Tenon fibroblasts. Fibroblast death was quantified using a lactate dehydrogenase release assay. The effect of Fas and TNF-receptor signaling was evaluated using Fas-specific antibodies and soluble TNF-alpha. RESULTS: Tenon fibroblasts constitutively express Bcl-2, Bax, and Bcl-x in culture. Mitomycin-C (0.4 mg/mL) induced a small but consistent increase in the expression of all three proteins. Tenon fibroblasts express low levels of Fas but are resistant to the effects of Fas-receptor ligation. Mitomycin-C (0.01-1.0 mg/mL) led to a significant increase in Fas expression at all concentrations tested (P < 0.01). Pretreatment with mitomycin-C (0.4 mg/mL) rendered fibroblasts susceptible to agonistic anti-Fas monoclonal IgM antibodies (50-500 ng/mL) and led to a further 50% reduction in viable fibroblasts at 48 hours, compared with mitomycin-C alone (P < 0.05). Antibodies that block the Fas receptor did not inhibit mitomycin-C-induced apoptosis. CONCLUSIONS: Mitomycin-C alters apoptosis gene expression and primes fibroblasts to the effects of Fas receptor ligation. Factors other than the level of Fas receptor expression modulate the response to Fas receptor signaling. Determining the signals that regulate fibroblast apoptosis may help to refine therapeutic strategies for switching off the subconjunctival healing response and maintaining intraocular pressure control.

Antibiotics, Antineoplastic↗
PubMed2005

Pterygium surgery with mitomycin and tarsorrhaphy.

PURPOSE: To determine if a pterygium surgical procedure consisting of minimal conjunctival removal, excision of the hypertrophic subconjunctival fibrovascular tissue, application of mitomycin 0.25 mg/mL for 1 minute combined with temporary nasal tarsorrhaphy, and use of postoperative dexamethasone/antibiotic drops achieves the following: safely simplifies pterygium removal, controls the early side effects of mitomycin, reduces the rate of recurrence, and lessens the need for conjunctival transplantation. METHODS: Twenty eyes in 19 patients underwent the procedure with use of mitomycin; 15 eyes had primary and 5 had recurrent pterygia. These were compared with a previous group of 28 eyes in 26 patients that underwent pterygium/tarsorrhaphy surgery without use of mitomycin; 20 eyes had primary and 8 had recurrent pterygia. Postoperatively, all eyes in both groups were treated with dexamethasone/antibiotic drops. RESULTS: In the mitomycin group, with an average follow-up of 12.1 months, 19 eyes healed uneventfully; there have been no recurrences. The nonmitomycin group, with an average follow-up of 42.6 months, has had nine recurrences (32%); four required a second procedure. Recurrence was significantly lower in the mitomycin group (P = .006). Conjunctival healing, as reflected in the time from surgery until tarsorrhaphy opening, was significantly delayed in the mitomycin group, 36.7 versus 17 days (P = .001). The delay in conjunctival healing may explain the complications associated with the use of mitomycin in pterygium surgery. CONCLUSION: Minimal conjunctival removal, extensive fibrovascular tissue excision, 1-minute application of mitomycin 0.25 mg/mL, temporary nasal tarsorrhaphy, and frequent application of dexamethasone/antibiotic drops postoperatively provided a safe and successful approach to pterygium management in this series.

Adult↗
PubMed1985

Stability of mitomycin admixtures.

The stability of mitomycin in admixtures for continuous intravenous infusion was studied. Mitomycin was reconstituted and diluted to 50 micrograms/mL in polyvinyl chloride minibags containing 5% dextrose injection 50 mL or 0.9% sodium chloride injection 50 mL. Additional mitomycin admixtures were reconstituted with a buffer solution containing monobasic and dibasic sodium phosphate; these were diluted with 5% dextrose injection only. Admixtures were stored at room temperature (27-30 degrees C) and refrigerated temperature (5 degrees C) for 120 days. Mitomycin concentrations in each admixture were tested by high-performance liquid chromatography (HPLC) immediately after admixture and at intervals during storage. Ultraviolet spectra were determined at the same time as HPLC analysis, and the admixtures were visually inspected and tested for pH. Mitomycin concentrations decreased rapidly in the unbuffered admixtures; after 12 hours at room temperature, less than 26% of the drug remained in the dextrose admixture. When the unbuffered admixtures were refrigerated for 12 hours, the mitomycin concentrations decreased 10% in the sodium chloride admixtures and 33% in the dextrose admixtures; after 24 hours, the percentages of drug loss were 23% and 42%, respectively. Mitomycin concentrations in the buffered admixtures showed no substantial decrease during 120 days at 5 degrees C. At room temperature, concentrations decreased 10% after 15 days. When the admixture is buffered to a pH of approximately 7.8, mitomycin is stable in 5% dextrose injection for up to 15 days at room temperature and at least 120 days at 5 degrees C. Unbuffered mitomycin admixtures should not be stored or administered by prolonged i.v. infusion.

Chromatography, High Pressure Liquid↗
PubMed1995

[Effect of mitomycin C on aqueous humor flow after trabeculectomy].

The intraoperative application of the antimetabolite mitomycin C has been recommended extensively in the literature for trabeculectomy in eyes with poor prognosis glaucoma. The modulation of wound healing with the antimetabolite mitomycin C has increased the success and predictability of filtration surgery. However, eyes in which mitomycin C is applied topically via a sponge during surgery bear the risk of developing postoperative hypotony and a decrease in visual acuity. Anterior chamber fluorophotometry (Fluorotron Master II, Coherent, Palo Alton) was used to study the effect of trabeculectomy with and without mitomycin C on the aqueous humour dynamics in glaucomatous eyes 6 months postoperatively. A 0.5-mg/ml solution of mitomycin C was applied topically via a sponge under the conjunctival flap. In a second group the same type of limbus-based flap was performed without the use of mitomycin C. The subsequent procedure was identical in both groups. Six months after surgery the eyes without mitomycin C revealed normal aqueous humour flow during the afternoon hours, comparable with the unoperated fellow eyes (mean 2.1 microliters/min). Eleven eyes treated with mitomycin C showed a reduction of aqueous humour flow of about 56% (mean 0.9 microliter/min) when compared with the unoperated contralateral eye and an age-, race- and sex-matched group. The fluorophotometric data suggest that the significant reduction of aqueous humour flow is the reason for the hypotony seen in glaucomatous human eyes following trabeculectomy with mitomycin C.

Adult↗
PubMed1997

Mutations induced in a shuttle vector plasmid exposed to monofunctionally activated mitomycin C.

Reductive activation of mitomycin C leads to its covalent binding to DNA, forming monoadducts and cross-links. The cytotoxicity of mitomycin C has been attributed to cross-link formation, whereas monoadducts are assumed to cause mutagenicity. We have developed a 32P-postlabeling technique to measure mitomycin C DNA adducts. Using this technique, we have measured monoadduct formation in the shuttle vector plasmid pSP189 and have determined mutations induced by monoadduct formation. The shuttle vector plasmid was incubated with mitomycin C under conditions favoring monofunctional activation of mitomycin C. The plasmid was then replicated in human Ad293 cells, rescued in bacteria, and analyzed for mutations in the supF tRNA gene sequence of pSP189. One major mitomycin C/DNA adduct was observed by 32P-postlabeling and was characterized as a monoadduct of guanine. When pSP189 was exposed to monofunctionally activated mitomycin C, increases in adduct levels and mutation frequency were found to be related to mitomycin C concentration. The majority of the mutations involved single bases, with base substitutions making up 59.1% of the total mutations observed. Of the base substitutions, 67.2% were transversions and 32.8% were transitions, with nearly 80% of all base substitutions involving G:C base pairs. Deletions, either as single bases or large deletions, also involved G:C base pairs the majority of the time. The observed bias of mutations at G:C and the formation of a mitomycin C/DNA monoadduct involving guanine suggests that monoadduct formation may be responsible for the mutations.

Base Sequence↗
PubMed1997

Topical mitomycin-C for pterygia: is single application appropriate?

BACKGROUND AND OBJECTIVE: Mitomycin-C has been shown to dramatically reduce pterygium recurrence rates; however, its use has been associated with serious complications, especially in higher cumulative doses. The authors investigated the safety and efficacy of progressively reducing dosages of mitomycin-C as an adjunct to pterygium surgery. PATIENTS AND METHODS: Four hundred eighty-one consecutive primary and recurrent pterygia were surgically excised in a prospective nonrandomized trial using five different mitomycin-C dosages. Recurrence was defined as fibrovascular tissue over the corneoscleral limbus onto clear cornea in the area of previous pterygium excision. RESULTS: Seventy-seven patients in a control group without mitomycin-C had a recurrence rate of 65% with a mean follow-up of 33 months. A group of 77 patients treated with 0.4 mg/ml of mitomycin-C, four times per day for 2 weeks, had a recurrence rate of 2.5% with 6 (10%) serious complications (mean follow-up 34 months). A group of 22 patients treated with 0.2 mg/ml of mitomycin-C, four times per day for 10 days, had a recurrence rate of 55% with 3 (7.3%) non-vision-threatening complications (mean follow-up 32 months). A group of 16 patients treated with 0.2 mg/ml of mitomycin-C intraoperatively for 3 minutes without conjunctival closure had a recurrence rate of 44% with no complications (mean follow-up 35 months). Finally, a group of 289 patients treated with 0.2 mg/ml of mitomycin-C intraoperatively for 3 minutes with conjunctival closure had a recurrence rate of 2.7% and no complications (mean follow-up 26 months). CONCLUSION: Although the authors' results with single application are encouraging, the use of mitomycin for pterygia remains controversial. The biologic potency of this agent, the duration of its action, and the dearth of large-scale controlled, randomized trials demand cautious individual judgment by the surgeon when considering the use of this potent drug.

Administration, Topical↗
PubMed1990

Addition of a hypoxic cell selective cytotoxic agent (mitomycin C or porfiromycin) to Fluosol-DA/carbogen/radiation.

In an effort to develop effective combination treatments for use with radiation against solid tumors, the cytotoxic effects of the addition of mitomycin C or porfiromycin on treatment with Fluosol-DA/carbogen (95% O2/5% CO2) breathing and radiation in the FSaIIC tumor system were studied. In vitro mitomycin C and porfiromycin were both preferentially cytotoxic toward hypoxic FSaIIC cells. After in vivo exposure, however, the cytotoxicity of mitomycin C toward single cell tumor suspensions obtained from whole tumors was exponential over the dose range studied, but for porfiromycin a plateau in cell killing was observed. With Fluosol-DA/carbogen breathing and single dose radiation, addition of either mitomycin C or porfiromycin increased the tumor cell kill achieved at 5 Gy by approximately 1.2 and 1.0 logs, respectively. Less effect was seen with addition of the drugs at the 10 and 15 Gy radiation doses. In tumor growth delay experiments, the addition of either mitomycin C or porfiromycin to Fluosol-DA/carbogen breathing and radiation resulted in primarily an additive increase in tumor growth delay. The survival of Hoechst 33342 dye-selected tumor cell subpopulations indicated that Fluosol-DA/carbogen breathing increased the cytotoxicity of radiation (10 Gy) more in the bright cell subpopulation (4-fold) than in the dim cell subpopulation (2-fold) resulting in an overall 4-fold sparing of the dim subpopulation. Mitomycin C and porfiromycin were both more toxic toward the dim cell subpopulations. Addition of mitomycin C or porfiromycin to Fluosol-DA/carbogen breathing and radiation (10 Gy) resulted in a primarily additive effect of the drugs and radiation killing in both tumor cell subpopulations. Thus, with mitomycin C/Fluosol-DA/carbogen and radiation there was a 2-fold sparing of dim cells and with porfiromycin in the combined treatment a 1.6-fold sparing of the dim cell population. Our results indicate that treatment strategies directed against both oxic and hypoxic tumor subpopulations can markedly increase the tumor cell kill achieved by radiation.

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