Mitomycin C Injection Research Articles

Comparison between the micronucleus frequencies of kidney and gill erythrocytes in tilapia fish, following mitomycin C treatment

The frequencies of mitomycin C and cyclophosphamide-induced kidney and gill erythrocyte micronuclei were compared in Tilapia rendalli and Oreochromis niloticus. Cyclophosphamide (CP) and mitomycin C (MMC) were previously used to investigate fish sensitivity to micronuclei induction in kidney erythrocytes. Fish were treated with a single dose of cyclophosphamide (40 mg/kg) or mitomycin C (2 mg/kg). Peripheral blood samples and kidney blood samples were obtained, 1, 2, 3, 5, 7, and 15 days after the intra-abdominal injection of MMC. T. rendalli showed to be more sensitive than O. niloticus to micronuclei production. Both compounds were used at the maximum tolerated dose (MTD), and mitomycin C proved to be more toxic than cyclophosphamide. The frequency of micronucleated erythrocytes observed varied significantly among the treated individuals. The difference between the kidney and gill micronuclei frequencies was not significant. Higher levels of micronucleated erythrocytes were observed in Tilapia rendalli than in O. niloticus. T. rendalli produced erythrocytes with deformed nuclei, which O. niloticus did not.

Anticlastogenic activity of cacao: inhibitory effect of cacao liquor polyphenols against mitomycin C-induced DNA damage

Oxidative DNA damage has been implicated as a factor playing a role in mutagenesis and carcinogenesis. We investigated the anticlastogenic activity of cacao: the inhibitory effect of cacao liquor polyphenols on DNA strand cleavage induced by mitomycin C (MMC) in vitro and the anticlastogenic effect of cacao liquor extract against formation of micronuclei induced by MMC in bone marrow cells and peripheral blood cells of mice. In the DNA strand cleavage test, cacao liquor polyphenols inhibited cleavage of RFI DNA. In the micronuclei test, the frequency of occurrence of micronucleated cells among bone marrow cells and peripheral blood cells were reduced significantly when cacao liquor extract was administered orally to mice 6 h before intraperitoneal injection of MMC. These findings suggest that cacao liquor polyphenols are effective in preventing DNA damage, and one of the mechanisms of action might involve scavenging of active oxygen radicals generated in reactions initiated by MMC.

Intraocular pressure reduction after subconjunctival mitomycin-C in absolute glaucomatous eyes

This study investigated the intraocular pressure (IOP) lowering effect of subconjunctival injection of mitomycin-C in human eyes blinded by glaucoma. Twenty eyes received injection of 1 mg of mitomycin-C and were followed up for 2 months. A statistically significant decline in IOP was observed until day 30 in all patients. The IOP-lowering effect of 1 mg of subconjunctivally injected mitomycin in patients with intractable glaucoma appears to be temporary.

Intrastromal Holmium Laser Keratostomy: Long-Term Results

A new filtering procedure, the Intrastromal Holmium Laser Keratostomy (ILK) has been developed. A laser canal is created intrastromally in the cornea anterior to Schwalbe's line in the floor of a corneo-scleral tunnel incision made with a knife from the corneal site. Theoretically, the complications of the conventional Subconjunctival Holmium Laser Sclerostomy (SLS) can thus be avoided. Experimental and clinical evaluation of the new procedure, as well as clinical long-term results are presented. The ILK was evaluated experimentally on bank eyes and clinically using postoperative Ultrasound Biomicroscopy (UBM). The clinical long-term effect was evaluated by a follow-up of the first 22 ILK performed on 17 eyes in 17 consecutive patients with complicated, refractory primary and secondary open angle glaucoma. Preoperative subconjunctival mitomycin-C injection (0.02 mL of 0.2 mg/mL) was used. The experimental and clinical evaluations show that the collateral thermal tissue coagulation made by the Holmium laser in ILK probably is an advantage, because the subsequent shrinkage prevents postoperative self sealing of the laser canal. Complete surgical success without medication and reoperations was reached in 63% of the eyes with a mean observation time of 22.5 months (range: 16.6-26.7 mos.). Any failure appeared within the first 10 months. Only 13% of the eyes had early iris incarcerations, there were no late incarcerations. Twenty-five percent had temporary shallow anterior chambers. The mitomycin-ILK procedure has shown obvious better results than the conventional SLS technique due to a considerable reduction in postoperative complications. Since the present material further developments in the ILK technique has made this procedure still more attractive.

Effects of subconjunctival injection of mitomycin-C on iridial circulation in rabbits

PURPOSE. To determine the effects of a subconjunctival injection of mitomycin-C (MMC) on iridial circulation in rabbits. METHODS. Dutch rabbits anesthetized with pentobarbital received a 0.2-ml subconjunctival injection of 0.4 mg/ml or 0.1 mg/ml MMC; the contralateral eye received 0.2 ml physiological saline. Intraocular pressure (IOP) and NB iris, a quantitative index of iridial tissue blood velocity, were measured up to 24 hours after treatment. RESULTS. At a dosage of 0.4 mg/ml MMC, NB iris obtained from the iridial area adjacent to the injection site decreased significantly by 13.6% and 18.6% at 1 and 2 hours (P = 0.03, 0.01, respectively) after treatment; NB iris obtained on the contralateral side of the injection showed no significant change. In eyes treated with 0.1 mg/ml MMC, NB iris did not change significantly. The mean IOP was significantly lower by 3.1, 3.0, and 1.8 mm Hg at 6, 12, and 24 hours after the 0.4 mg/ml injection of MMC compared with the fellow eyes (P = 0.03, 0.01, and 0.03, respectively), the IOP decreased by 1.7 mm Hg at 4 hours in the eyes treated with 0.1 mg/ml MMC (P = 0.04). CONCLUSIONS. Subconjunctival injections of 0.2 ml of 0.4 mg/ ml MMC caused not only a significant decrease of IOP but also a transient but significant effect on iridial circulation.

Antimetabolite Use in Revising Failing Filtering Blebs

This article evaluates the efficacy of a subconjunctival injection of mitomycin-C (MMC) followed by needling of the scar tissue to restore bleb function. By means of preoperative ultrasonic biomicroscopy, all the eyes in this study were categorized into one of three groups: Group I (bleb present), Group II (minimal bleb), and Group HI (no bleb present). This classification was carried out to try to control for differences in bleb appearance that may correlate with bleb function. The eyes in Group I (bleb present) had a statistically significant decrease in their intraocular pressure (IOP) from the initial IOP (Po) that Groups II (minimal bleb) and III (no bleb) eyes did not show. The final lOPs (Pf) for all three groups were statistically similar, suggesting that MMC bleb needling is more effective in lowering IOP when there still is a bleb present. If this is true, early intervention in the form of MMC bleb needling affords the surgeon the best opportunity to successfully restore the function of the failing bleb.

Subconjunctival Injection of Low Doses of Mitomycin C: Effects on Fibroblast Proliferation

We evaluated the effect of low doses of mitomycin C (MMC) in subconjunctival injection on fibroblast viability. Eighteen rabbits received subconjunctival injections: group 1 was injected with balanced salt solution (BSS), group 2 received MMC 0.025 mg, and group 3 MMC 0.005 mg. Tissue samples were taken 1 h after the injection (conjunctiva, sclera and cornea at 0 and 90 °) and cultured. The average scleral and conjunctival outgrowth in the MMC-treated groups was significantly inferior to the outgrowth of the samples treated with BSS. Subconjunctival injections of MMC (0.025 and 0.005 mg) have an inhibitory effect on conjunctiva at 0 ° and on scleral fibroblast populations.

Long-term effects of postoperative subconjunctival injections of mitomycin-C in the rabbit eye.

Single or multiple subconjunctival injections of mitomycin-C (MMC) may offer one way of establishing the total dosage of MMC more accurately. The method also allows re-applications later postoperatively. In this experimental, randomized prospective study we compared the effects of a single intraoperative application of MMC at the filtering site and a single postoperative subconjunctival injection of the drug. The left eyes of 32 pigmented rabbits were divided into two groups. In the first group we applied MMC intraoperatively (IO) with a 4 x 1 mm surgical sponge soaked in a MMC solution (0.5 mg/ml). In the second group we injected 0.4 ml of the same solution subconjunctivally (SC) immediately after (conjunctival) suture. Post-operative evaluation was carried out every day during the first week, then every three days until day 58. Survival analyses were done for intraocular pressure (IOP) and bleb failure. Log-rank tests were used to compare survival differences between the groups. The IO group showed longer survival parameters than the SC group (p < 0.05), both in the control of IOP and as regards blebs. The histological persistence of fistulas was similar. The IO group, however, had a higher incidence of undesirable side effects. Our findings suggest IO application of MMC is more effective in reducing fibroblast ingrowth. However, subconjunctival application offers certain advantages such as the possibility of repeating the treatment postoperatively and, therefore, using a smaller initial dose.

Protection of mitomycin C induced skin extravasation with the nitroxide, 3-carbamoyl-PROXYL (3-CP)

Extravasation tissue injury from chemotherapeutic drugs is a serious clinical problem. A swine model has been useful for studying skin extravasation and evaluating potential antidotes. Mitomycin C (MMC) skin extravasation was studied. Nitroxides, a class of compounds which are protective against a variety of oxidative stresses in vitro, including MMC, were tested as antidotes. Miniature swine were anesthetized and given intradermal (ID) injections of MMC. MMC alone caused skin necrosis and ulceration. Several nitroxides were screened as protectors of MMC induced skin necrosis. 3-carbamoyl-PROXYL (3-CP) was the lone nitroxide which protected if given 5 min after extravasation. Administration of 3-CP 10 min after MMC injection was not protective. In vitro studies with monolayered V79 cells showed that 3-CP had a direct protective effect against MMC cytotoxicity in a concentration-dependent fashion. Therefore, in the swine model doses of 3-CP ranging from 25-100 mM were tested and found to protect against MMC skin necrosis 90 days after injection. Histologic sections of the 3-CP- and MMC-treated pig skin showed a marked reduction in the degree of acute inflammation and the absence of deep dermal scarring when compared to MMC alone.

Indications for and Complications of Mitomycin-C in Pterygium Surgery

The purposes of this study are to examine the complications and results of a novel approach to the use of mitomycin-C in pterygium surgery; to identify the lowest effective dosage required to prevent recurrence; and to select those high-risk pterygia that could benefit from mitomycin-C use. One hundred thirty-five eyes of 128 patients considered at high risk for recurrence of pterygium were treated with a single, intraoperative, subconjunctival injection of mitomycin-C at the site of excision. Three different dosages-0.2, 0.1, and 0.05 ml-at a strength of 0.5 mg/ml were used. The eyes were observed for 10 months to 3 years. There were only two recurrences (1.5%); both occurred in eyes that had undergone previous pterygium surgery. One recurrence happened with the 0.2-ml dosage, and the other with the 0.1-ml dosage. These recurrences occurred in association with early wound dehiscence, which essentially became a bare sclera susceptible to pterygium regrowth. Complications included temporary and prolonged discomfort, tearing, hyperemia, subconjunctival hemorrhage, wound dehiscence, and pigment accumulation. No vision-threatening side effects were noted. The persistence and intensity of discomfort noted at the higher dosage has prompted these authors to suggest that only high-risk pterygia should receive mitomycin-C. Conjunctival flaps should always be used to cover the sclera up to the limbus and to localize the mitomycin-C to prevent its migration. A single dose of not more than 0.05 ml at a strength of 0.5 mg/ml subconjunctivally gives the same results as multiple drops, but with far less morbidity.

The effect of a selective 5-lipoxygenase inhibitor, zileuton, on tissue damage in acute colonic inflammation in rats.

Though the mechanism of tissue damage induced by colonic inflammation in ulcerative colitis is unknown, it has been established that the inflammatory mediator and potent neutrophil (PMN) chemotaxin, leukotriene B4(LTB4), is present in elevated amounts in the inflamed mucosa. The unique role of 5-lipoxygenase in the production of leukotrienes has made it a target for inhibition. This study used a rat model of acute colonic inflammation induced by a single IP injection of Mitomycin-C to test the efficacy of a specific and potent 5-lipoxygenase inhibitor zileuton in the treatment of colonic inflammation. We hypothesized that after inducing colitis in rats with mitomycin-C, the administration of oral zileuton would inhibit leukotriene production, thus preventing PMN infiltration and subsequent tissue damage. Zileuton decreased colonic tissue damage as measured by Histological score. However, zileuton did not significantly decrease neutrophil infiltration measured by mucosal PMN or myeloperoxidase (MPO) levels. Although zileuton was successful in significantly decreasing the frequency of severe colitis in our model, the fact that the decrease in PMN count and MPO level was not statistically significant suggests that another mechanism may be involved in its anti-inflammatory effect.

Pharmacokinetics of intraarterial mitomycin C in the chemoembolisation treatment of liver metastases

1. 1. The pharmacokinetics of mitomycin C (MMC) were investigated in 12 colorectal cancer patients with liver metastases undergoing chemoembolisation. Hepatic artery branches were embolized using polyvinylalcohol microspheres (150–250 μm) before applying 20 mg MMC in 4–8 min. 2. 2. Serum MMC concentrations were determined from peripheral venous blood samples by reversephase HPLC using ultraviolet detection. Pharmacokinetic parameters were computed assuming an open two-compartment model. 3. 3. Pharmacokinetic parameters were similar to values given in the literature for intravenous (IV) or intraarterial (IA) bolus MMC injections ( T max = 7.0 min following the beginning of MMC infusion, V ss=0.57 1/kg, C1=8.9 ml/min.kg, T 1 2 a = 8.3 min , T 1 2 β = 58.6 min ). 4. 4. The area under the serum concentration-time-curve (AUC), standardized by the MMC amount injected, was similar to values reported in the literature for IV or IA bolus injections. There is no evidence for reduced systemic MMC exposure following the embolization procedure used.

Anticlastogenic effects of galangin against mitomycin C-induced micronuclei in reticulocytes of mice

We investigated the suppressive effect of galangin on the induction of micronucleated reticulocytes (MNRETs) by mitomycin C (MMC) in mouse peripheral blood. When galangin was given to mice 24 h before the intraperitoneal injection of MMC (1 mg/kg), a more marked decrease in the frequency of MNRETs was observed than in mice with simultaneous and post-treatment of galangin. On the other hand, when galangin was given to mice for 7 consecutive days before MMC injection, galangin showed potent anticlastogenic effects, even at the lowest dose level of 0.1 mg/kg. Results from our in vivo studies indicate that galangin is capable of suppressing the clastogenic activity of the direct acting MMC. Together with our earlier observations, it appears that galangin is capable of protecting cells from toxic effects of a variety of hazardous chemicals. Therefore, galangin may be an useful chemopreventive compound.

The toxicology of mitomycin C on the ciliary body.

Over the past few years, the use of mitomycin C (MMC) to reduce surgical failures following filtering procedures has largely increased. After topical application, significant amounts of MMC can be detected intraocularly. In both rabbit and human eyes, a reduction of the normal and elevated intraocular pressures could be achieved with subconjunctival injections of MMC without filtering procedures. Histopathologic examination of the ciliary body in a human eye shortly after surgery with MMC revealed moderate, diffuse toxic changes of the two layers of the ciliary epithelium. By fluorophotometry, eyes after trabeculectomy with MMC had a decreased production of aqueous humor compared with eyes that underwent trabeculectomies without antimetabolites. Independent studies suggest that the toxicity of MMC for the ciliary epithelium may be a significant factor contributing to postoperative hypotony.

The Effects of Dimethly Sulfoxide and Sodium thiosulfate for the Prevention of Tissue Necrosis due to Extravasation of Mitomycin-C

Extravasation of toxic chemotherapeutic agents cause severe skin ulceration and necrosis which often need secondary surgical intervention. Still, there were not established antidote agent in case of extravasation with mitomycin-c. Dimethyl sulfoxide is known as an effective chemical scavenger of toxic hydroxyl free radical and sodium thiosulfate also was demonstrated significant protector from mitomycin-c induced ulceration by a few experimental studies. Author investigated necrotic area of mitomycin-c injected site and compare to the effectiveness of topical treatment with dimethyl sulfoxide and intradermal injection of sodium thiosulfate according to starting times, forty five mice were divided into 3 groups. Control group(n=5) had no treatment after subcutaneous injection of mitomycin-c. Experimental group I and II were 20 mice treated dimethyl sulfoxide and sodium thiosulfate, respectively. Depending on the starting time of treatment, group I and II were subdivided into 1, 2, 3 and 4 as immediate, 6 hours, 12 hours and 24 hours after mitomycin-c injection. Histologic studies of the necrotic area and survival area after treatment were performed using hematoxylin-eosin staining. The mean necrotic area of group I was significantly decreased depending on the starting time of treatment compared with control group(p

Preoperative Mitomycin-C Subconjunctival Injection and Glaucoma Filtering Surgery

Intraoperative mitomycin-C application has been well accepted recently as a useful adjunctive procedure to enhance the filtering effect in glaucoma surgery. However, the exact dose of mitomycin-C left after such a procedure in the ocular tissue is variable and unclear. It is important to determine such residual because of potential long-term toxicity of mitomycin-C to the eye. Based on previous successful experience using preoperative mitomycin-C subconjunctival injection in the THC-YAG laser sclerostomy on rabbits, the effect of intraocular pressure (IOP) control and its clinical observation was studied in six eyes of six refractory and high risk glaucoma patients by subconjunctival 1.2 micrograms to 3.6 micrograms mitomycin-C injection 24 to 72 hours prior to classic, routine, limbal-based trabeculectomy surgery. After 18 months of satisfactory clinical observation of the first eye for IOP, functioning bleb appearance and smooth clinical course, the same procedure was used on an additional five eyes, with a follow-up period of more than five months. Average IOP was reduced from 27.8 mm Hg (range 24 to 34 mm Hg) preoperatively to 9.5 mm Hg (range 5 to 14 mm Hg) postoperatively, with a smooth clinical course. The advantages of such preoperative subconjunctival mitomycin-C injection are emphasized here.

Improvement of mitomycin C- and cyclophosphamide-induced thrombocytopenia and leucocytopenia by prior treatment with deoxyspergualin in dogs.

Deoxyspergualin (DGS) is a new immunosuppressant which has shown inhibitory haemopoietic activity. We investigated the myeloprotective effect of DSG against the haemopoietic injury of mitomycin C (MMC) or cyclophosphamide (CYC) by measuring peripheral blood cell numbers in dogs. DSG given at 5 mg/kg on days 3, 2 and 1 before, or at 10 mg/kg on either days 2 and 1 before or on day 1 before and the day of injection of MMC at 0.25 mg/kg ameliorated both the thrombocytopenia and leucopenia caused by MMC. This ameliorative effect was more evident on platelet counts than on white blood cell counts. In addition, the leucopenia and thrombocytopenia induced by a single injection of CYC at 10 mg/kg was also ameliorated by prior DSG administration. These findings suggest that DSG may be useful in protecting against the haemopoietic damage induced by chemotherapeutic agents in the treatment of cancer.

The clastogen-suppressing effects of green tea, Po-lei tea and Rooibos tea in CHO cells and mice

The suppressing effects of crude extracts of three kinds of tea - green tea (GT) from Japan, Po-lei tea (PT) from China, and Rooibos tea (RT) from South Africa - on the induction of chromosome aberrations in cultured CHO cells and mice were studied. When CHO cells were exposed to each tea extract in the presence of rat liver microsomal enzymes (S9 mix) together with benzo[ a]pyrene (B(a)P) or mitomycin C (MMC), a decrease in the frequency of chromosome aberrations was observed. PT and RT, but not GT, also suppressed the induction of chromosome aberrations by MMC in the absence of S9 mix. When cells were treated with tea extract after B(a)P or MMC treatment, RT suppressed the induction of chromosome aberrations in the presence and absence of S9 mix whereas GT and PT showed suppressing effects only in the presence of S9 mix. These data suggest that catechines, well-known antimutagens in tea samples, might account for the inhibitory effect in the case of GT and PT. Since RT contains few catechines, several unknown antimutagenic components could be responsible for its effect. The antimutagenic effects of tea extracts at concentration levels consumed by humans were examined in mice using micronucleus induction with B(a)P or MMC. When mice received oral gavage of 0.2% GT, 0.1% PT, and 0.1% RT at 1.0 ml/mouse 6 h before intraperitoneal injection of MMC, a decrease in the frequency of micronuclei was observed. The induction of micronuclei by B(a)P was suppressed by oral dosage of GT, PT and RT at 1.0 ml/mouse/day for 28 days. This was not due to a delay in the maturation of micronucleated reticulocytes. In conclusion, intake of tea might suppress the mutagenic activity of certain potent mutagens in human beings.

Organotins are co-clastogens in a whole mammalian system

The frequency of micronuclei induced by mitomycin C (MMC) in mouse peripheral reticulocytes was enhanced by treatment with organotins: bis(tri- n-butyltin) oxide (TBTO) and triphenyltin chloride (TPTC). TBTO and TPTC did not themselves induce micronucleated reticulocytes (MNRETs) in mouse peripheral blood. When 50 mg/kg TBTO or 100 mg/kg TPTC was given orally to mice simultaneously with an intraperitoneal (i.p.) administration of 1 mg/kg MMC, however, TBTO and TPTC caused about 55% and 51% increases, respectively, in MMC-induced a synergistic MNRET frequency. Organotin administration 3 or 6 h before and 3 h after MMC injection also caused enhancement of MNRET frequency. These results demonstrate that TBTO and TPTC act as co-elastogens in a whole mammalian system.

THC

Subconjunctival fibrosis is one of the major causes of most bleb failures. To inhibit the wound-healing process and to achieve a better intraocular pressure (IOP) lowering effect as well as bleb formation, we performed a sclerostomy using a THC:YAG laser (thulium, holmium, and chromium-doped yttrium-aluminum-garnet crystal) and a subconjunctival injection of mitomy-cin-C given 24 h or 5 days before a filtering operation or soon after the filtering process in rabbits. A 1-mm conjunctiva wound was made 12 mm away from the sclerostomy site to allow for entry of an optic probe for delivering energy. Forty-eight rabbits were divided into four groups. Group I received a subconjunctival injection of 0.2 ml of 0.2 mg/ml of mitomycin-C 24 h before the operation. The same dosage of mitomycin-C was given to Group II 5 days before the operation and to Group III immediately following the operation. Group IV served as a control, and only 0.2 ml of normal saline solution was given 24 h preoperatively. One eye of each rabbit was randomly selected for the experiment, while the other eye served as a control. The bleb lasted 30.9 $pM 15.7 days in Group I, 16.0 $pM 6.4 days in Group II, 15.5 $pM 6.5 days in Group III, and 2.3 $pM 0.7 days in Group IV. The IOP lowering effect was parallel to bleb formation. The results demonstrate that a subconjunctival mitomycin-C injection given 24 h before a filtering operation is more effective in prolonging the filtering effect produced by the THC:YAG laser than one given postoperatively.