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Right corneal melting and scleral necrosis developed in a 77-year-old man 5 months after pterygium excision followed by topical administration of mitomycin C drops (0.4 mg/mL) for 4 weeks. We believe that these were delayed complications of the mitomycin C therapy, and we caution against prolonged use of the drug postoperatively.
OBJECTIVES: This single-institution study evaluates the feasibility of accelerated fractionation radiotherapy (AF) with and without mitomycin C (MMC) in the treatment of locally advanced head and neck cancer. PATIENTS AND METHODS: Between May 1998 and October 2001, sixty patients with locally advanced stage III and IV of head and neck cancer were randomized into three treatment arms: (1) conventional fractionation radiotherapy (CF) (5 fractions per week); (2) accelerated fractionation radiotherapy (AF) (6 fractions per week); and (3) AF plus Mitomycin C (MMC). RESULTS: The 2-year overall survival (OS) of the whole group was 21%. The OS according to treatment arm was 23%, 20%, and 28% in CF, AF, and AF+MMC arms respectively (p<0.19). The 2-year loco-regional control (LC) rate was 22% for the whole group of patients. The LC was 10%, 25%, and 30% for the CF, AF, and AF+MMC respectively (p=0.27). The only significant parameters for OS and LC were performance status and pre-treatment hemoglobin level. Mucositis grades 3 & 4 occurred in 70% and 90% of the patients in the AF and AF+MMC arm respectively compared to 55% of patients in the CF arm (p=0.04). However the addition of MMC did not significantly increase the incidence or severity of mucositis between AF and AF+MMC (p=0.13). Hematological toxicity grades 3 & 4 were significantly higher after MMC (occurred in 40% of patients versus 10% and 5% in CF and AF arms respectively, p=0.04). There was no statistically significant difference in the incidence of grade 3 dryness of mouth (p=0.06), fibrosis (p=0.6), or lymphoedema (p=0.39) among the three arms. CONCLUSION: There was a trend for improvement of LC and OS rates with the use of AF and the addition of MMC to AF compared to CF radiotherapy, although the difference was not statistically significant. The small number of the patients in each treatment arm and the inclusion of multiple tumor sites may contribute to these statistically insignificant results. Accordingly we advise 85 to continue the trial with inclusion of a larger number of patients and restrict tumor sites to one major site.
Cisplatin-etoposide (CE) and mitomycin, ifosfamide and cisplatin (MIC) combinations are active conventional regimens in non-small cell lung cancer (NSCLC). In this retrospective study, we compared response rates, survival, duration of response, time-to-progression and toxicity of CE with MIC regimens in treatment of previously untreated patients with stage IIIB and IV NSCLC. We first determined the patients with NSCLC who had stage IIIB or IV and received CE or MIC between January 1997 and December 2002 in our clinic. Out of the eligible patients, 45 received MIC, 167 received CE. In addition 45 MIC patients, we included 46 of the 167 CE patients in the study by selecting one patient of every three patient randomly. In CE protocol, cisplatin 80 mg/m(2) on day 1 and etoposide 100 mg/m(2) on days 1, 2, 3 (every three weeks); in MIC protocol, mitomycin 6 mg/m(2), ifosfamide 3 g/m(2), cisplatin 50 mg/m(2) on day 1 (every three weeks) were performed. For statistical analysis, chi-square, t-test, Kaplan-Meier survival analysis, Cox regression analysis and logistic regression analysis were used by SPSS 11.5 computer program. The overall response rate was 33.3% in the MIC arm and 34.8% in the CE arm. A respective median survival was 28 weeks for the MIC arm and 35 weeks for the CE arm. Median duration of response and time to progression in each groups were 23 and 14 weeks in MIC arm and 32 and 22 weeks respectively. There was no statistical difference for response rates, duration of survival and response, time top progression and toxicity between the two arms. We consider that the combinations of MIC and CE have similar activity and they can be used confidently in advanced NSCLC.
Bladder cancer is the fifth most common cancer in the Western world and is on the rise. Most patients present with superficial disease and are treated by transurethral resection of bladder tumor. More than half of these patients experience recurrence with about 20% progressing to muscle invasive disease. Intravesical chemotherapy has been shown to decrease the risk of recurrence of bladder cancer. Mitomycin C has emerged as a major agent for an immediate post-resection intravesical instillation. This article reviews the literature on the mode of action, rationale for immediate adjuvant treatment with Mitomycin C and adverse effects associated with its use.
The production of virions by Chinese hamster kidney cells infected with SV 40 DNA is increased 10 to 100 fold by mitomycin C treatment. This observation has been confirmed for different cell clones. The optimum concentration of mitomycin C has been determined.
Sixty patients with Ta and T1 bladder cancer were randomized between treatment with resection only and resection and instillations with either Adriamycin or Mitomycin C. Treatment lasted for one year and patients were evaluated after a mean follow-up of 35 to 47 months if progression had not occurred. Mitomycin C was superior in reducing the recurrence rate. Progressive disease was observed in 17 patients regardless of therapy but in all patients DNA aneuploidy could be identified at a risk factor.
We report on 10 cases of bladder wall calcification after mitomycin C instillation. The cystoscopic and microscopic features of these lesions are described. In our view, these lesions can be ascribed to the use of mitomycin C instillation therapy immediately after TUR. Because they are asymptomatic and occasionally present features of tumor recurrence, biopsy is advocated to determine the true nature of these lesions.
This study shows that artificial increase in cell site leads to morphological normalization of transformed fibroblasts. Mouse L cells (clone 171/5) were used. As most transformed cells, they were poorly spread on the substratum, made only dot-like focal contacts with it, rounded quickly at room temperature and did not contain prominent actin cables. Giant cells were obtained by incubation of these cells in the medium supplemented with mitomycin C (0.15-0.20 mcg/ml). DNA synthesis and mitosis were blocked by this treatment, while protein synthesis was changing very slightly. As a consequence, the cell size increased dramatically from 3 to 11 days of the cell incubation in the mitomycin containing medium. The degree of cell spreading per mcg of protein increased significantly in the giant cells. These cells do not round after moderate cooling, and well developed system of actin cables and matured streak-like focal contacts associated with these cables are formed in them. These results, along with our previous data on the restoration of cell spreading and cytoskeleton structure in giant multinucleated cells, provide strong evidences that the increase in cell size per se can induce qualitative changes in cell morphology. It can be suggested that there are some scaling-dependent factors regulating the processes of cytoskeleton assembly and formation of cell-substrate contacts.
Through the extensive investigation of new mitomycin C (MMC) derivatives, several compounds with disulfide at N-7 were found to show activities superior to MMC against murine Sarcoma 180 solid tumor. Among them, 7-N-[[2-[[2-(gamma-L-glutamylamino)ethyl]dithio]ethyl]]- mitomycin C (KW-2149) was selected for further evaluation of antitumor activity and toxicity in mice. KW-2149 exhibited activity superior to MMC in increasing survival of i.p. inoculated P388 leukemia-, M5076 sarcoma-, and B16 melanoma-bearing mice. KW-2149 administered i.v. also exhibited superior activity in inhibiting the growth of s.c. inoculated P388 leukemia, M5076 sarcoma, and colon 26 adenocarcinoma and in increasing survival of i.v. inoculated P388 leukemia- and M5076 sarcoma-bearing mice. Furthermore, KW-2149 remarkably increased the life span of MMC-resistant P388 leukemia- and L1210 leukemia-bearing mice. KW-2149 and MMC inhibited the growth of human tumors inoculated into nude mice. The activity of KW-2149 was prominent in human lung carcinoma Lu-65 and Lu-99, bladder carcinoma T24, and epidermoid carcinoma A431. KW-2149 was comparable to MMC in decreasing the number of WBC in the peripheral blood, and the thrombopenia induced by KW-2149 was mild and recovery was rapid. The in vitro anticellular spectrum of KW-2149 against 23 human tumor cell lines was similar to that of MMC. However, KW-2149 inhibited the growth of the cell lines at concentrations of 10- to 100-fold lower than MMC and showed efficient cytotoxicity against MMC-insensitive tumor cell lines. These included lung epidermoid carcinoma Calu-1, stomach carcinoma MKN-28, colon adenocarcinoma DLD-1, colon adenocarcinoma LoVo, bladder carcinoma HT-1197, sarcoma G-292, and melanoma SK-MEL-28 cells. These results indicate that KW-2149 bears interesting characteristics as a new anticancer drug and warrants further development.
1. Pterygia, triangular sheets of fibrovascular tissue that invade the cornea, have recurrence rates of 30% to 50% with currently available surgical procedures. 2. Mitomycin, an antimetabolite-antibiotic agent, has been reported to be effective in preventing recurrences of surgically excised pterygia when used adjunctively as eye drops. 3. Because mitomycin-C is an antineoplastic agent, appropriate policies and proper patient education are important.
Observations have been made of the multiple-drug resistance phenomenon in mitomycin-exposed cells in vitro. Collateral resistance to anthracyclines and Vinca alkaloids was demonstrated in mitomycin carbon-treated 1-1210 cells in vitro. However, because it has also been found that this resistance can be reversed with agents such as verapamil and progestogens, it may be possible to effect a similar reversal in vivo. A study is currently being performed in patients with colorectal cancer, in which the potential for reversal is being tested. The pharmacokinetics of ifosfamide result in high cytotoxic specificity which, along with its therapeutic range, makes it a particularly active agent in the treatment of non-small cell lung cancer. Its urotoxicity is effectively controlled by the coadministration of mesna, a uroprotective agent.
The intraneural injection of 25 micrograms/ml of mitomycin C produced a prolonged conduction block of delayed onset within the injected nerve. No change in electrophysiological parameters was seen for 6 days after injection, but thereafter a marked drop in the compound muscle action potential (CMAP) amplitude from stimulation proximal to the site of injection occurred, with recovery not being complete until day 97. CMAP amplitude from stimulation distal to the injection site remained unchanged. The reason for this prolonged period of conduction block was apparent from histological examination of the nerve. Light and electron microscope studies demonstrated Schwann cell death, clearly evident at day 8 and followed by subsequent macrophage removal of myelin and Schwann cell debris. Remyelination was not seen until day 40. Hence for periods of about 30 days naked axons persisted through the area of injection. Schwann cells associated with unmyelinated fibres were relatively unaffected, suggesting that myelinating Schwann cells were vulnerable to this agent by virtue of the metabolic processes associated with their myelin maintenance and renewal. These findings indicate that mitomycin C injected intraneurally provides an excellent model to study the effects of Schwann cell disease.
The mitomycins are antitumor antibiotics that are under investigation now for more than 30 years. Mitomycin C (MMC) is the best investigated subtype. It serves as a prototype for drugs with bioreductive alkylation, which is a unique feature of this class. MMC is mainly active under anaerobic circumstances. The pharmacokinetics are linear in a two-compartment model. The main toxicities of MMC are thrombocytopenia and leucocytopenia. Rare but severe side effects are a hemolytic uremic syndrome, pneumonitis and cardiac failure. MMC has a wide clinical antitumor spectrum with efficacy in various tumor types such as gastric cancer, pancreatic cancer, breast cancer, non-small cell lung cancer, cervical cancer, prostate cancer and bladder cancer. Still, the above mentioned side effects prevent a more widespread use. The most important features of the drug will be reviewed.
The bispecific monoclonal antibody (Bi-MAb) HRS-3/AP-1 was developed by somatic hybridization of the 2 mouse hybridoma cell lines HRS-3 and AP-1, which produce monoclonal antibodies with reactivity against the Hodgkin's- and Reed-Sternberg cell-associated CD30 antigen and alkaline phosphatase, respectively. After an active incubation with alkaline phosphatase, respectively. After an active incubation with alkaline phosphatase, purified whole immunoglobulin molecules and F(ab')2 fragments of the Bi-MAb were equally effective in converting a relatively noncytotoxic prodrug, mitomycin phosphate (MOP), into mitomycin alcohol, which was 100 times more toxic to the Hodgkin's- and Reed-Sternberg cell line L540 (CD30+) than MOP. The cytotoxic activity of MOP was unaffected when the cells were pretreated with either the Bi-MAb or the enzyme alone. The Bi-MAb HRS-3/AP-1 did not bind to HPB-ALL cells (CD30-) and was not able to activate MOP on these cells. In cocultivation experiments with HPB-ALL and L540 cells, the activation of MOP by the Bi-MAb HRS-3/AP-1 and alkaline phosphatase led to considerable cytotoxicity against the antigen-negative bystander cells. Thus, this immunotherapeutic approach might be effective in tumors in which not all the tumor cells express the respective tumor antigen.
Thirty-six patients with advanced carcinoma of the lung (30 with adenocarcinoma and six with large cell carcinoma) were treated with a combination of mitomycin C, Adriamycin, and cyclophosphamide (MAC) in a phase II study. Seven partial remissions were observed in adenocarcinomas, while none were seen in large cell carcinomas. The survival of patients in remission was clearly prolonged (P less than 0.01), with responders living a median of at least 39 weeks compared to 17 weeks for nonresponders. The combination was well-tolerated with moderate anorexia, nausea, vomiting, and alopecia. Myelosuppression was manageable but was more pronounced in previously chemotherapeutically treated patients. MAC offers a reasonable response rate in patients with adenocarcinoma of the lung with significant prolongation of survival; however, there was no significant advantage when compared to mitomycin C used as a single agent.
Twenty-eight patients with advanced squamous carcinoma of the uterine cervix received cisplatin, bleomycin, and mitomycin after failure of surgery and/or irradiation to control disease. Six patients (21%) achieved responses (two complete; four partial), ranging from 3 to 7+ months. Toxicity was acceptable for most patients; however, dose reduction because of myelosuppression was frequently required. Bleomycin was delivered by continuous iv infusion, and no significant pulmonary toxicity was observed. Although this combination of drugs has activity in advanced squamous carcinoma of the uterine cervix, the addition of cisplatin to bleomycin and mitomycin did not significantly increase the clinical response rate.
A total of 56 heavily pretreated patients with advanced breast cancer were treated with the combination mitomycin and mitoxantrone. Partial responses were seen in ten of 56 patients (18%), or ten of 44 (23%) completing two courses, while 18 (32%) had stable disease. Responses were seen in eight patients failing doxorubicin. The median duration of response was 26 weeks, with responders surviving a median of 37 weeks. A total of 59% of the courses were associated with World Health Organization grade 3 or 4 neutropenia (less than 1.0 X 10(9) cells/L). Nausea and vomiting were minimal. Mitomycin and mitoxantrone has activity in heavily pretreated patients with advanced breast cancer.
Forty-five patients with stage III M1 non-small cell bronchogenic carcinoma were treated with vinblastine (1 mg/m2 by iv bolus twice a day on 2 consecutive days) plus mitomycin (10 mg/m2 on Day 1). This treatment was repeated at 3-week intervals for three courses. Consolidation therapy with doxorubicin and cisplatin at doses of 50 mg/m2 each was administered to responders every 4 weeks for two courses, with subsequent vinblastine and mitomycin maintenance therapy every 6 weeks. Eleven partial remissions (24%) were achieved, with a median duration of remission of 16 weeks (range, 8-32) and a median survival of 19 weeks. No differences were seen in median duration of remission or survival by cell type or performance status.