Augmentation of vincristine cytotoxicity by megestrol acetate.

PURPOSE: To determine the effect of a semisynthetic progesterone, megestrol acetate (MA), on the cytotoxicity of various chemotherapeutic agents including vincristine, doxorubicin, actinomycin-D, taxol, vinblastine and colchicine in cell lines with or without P-gp expression. METHODS: Three cell lines with high P-gp expression (two colon cancer and one leukemia), and a control cell line with no P-gp expression were exposed to chemotherapeutic agents in the presence or absence of MA and drug sensitivity was determined using the MTT colorimetric assay. P-gp-170 expression was detected by flow cytometry using JSB-1 monoclonal antibody and the functionality of MDR expression was tested by rhodamine-123 uptake studies. In vitro drug accumulation studies were performed using [3H]-vincristine. The results were subjected to paired t-test analysis and 95% confidence intervals were determined in cytotoxicity tests. RESULTS: MA augmented the cytotoxicity of vincristine, but not doxorubicin, actinomycin-D, taxol, vinblastine or colchicine in the three P-gp-expressing cell lines, whereas verapamil augmented the cytotoxicity of doxorubicin and vincristine. MA did not augment the cytotoxicity of vincristine in the P-gp-negative HUT-102 cell line. CONCLUSION: MA augmented vincristine cytotoxicity in P-gp-expressing cell lines. However, this phenomenon did not occur with the other classic MDR drugs. Therefore, the augmentation of vincristine cytotoxicity by MA can be explained either by involvement of a different mechanism that coexists with the mdr-1 phenotype or by the presence of a different affinity or binding site on the P-gp molecule for MA compared to that for the other classic MDR drugs and verapamil.

Collection of mobilized blood progenitor cells for hematopoietic rescue by large-volume leukapheresis.

BACKGROUND: Mobilized blood progenitor cells rapidly reconstitute hematopoiesis in patients after dose-intensive chemotherapy. However, optimal timing and methods of mobilized blood progenitor cell collection have yet to be fully defined. STUDY DESIGN AND METHODS: The utility of large-volume leukapheresis (LVL; > 15 L blood processed) in collecting target doses of mononuclear cells (7 x 10(8)/kg) for use in autologous hematopoietic rescue was investigated. LVL was begun at a standardized interval (14 days) after a course of limited chemotherapy and subsequent daily recombinant human granulocyte-macrophage-colony-stimulating factor administration to mobilize blood progenitor cells into the circulation. With each LVL procedure, mononuclear cells, colony-forming units-granulocyte-macrophage (CFU-GM), burst-forming units-erythroid, mixed colonies, total clonogenic progenitor cells, and CD34+ cells collected per kg of patient weight were counted. After high-dose chemotherapy and infusion of cryopreserved mobilized blood progenitor cells, the days needed for neutrophils to reach levels of > 0.5 x 10(9) per L and for platelets to reach levels of > 20 x 10(9) per L were recorded. RESULTS: In 14 previously treated cancer patients, an average of 28.9 +/- 4.9 L of blood was processed per LVL (n = 35) to collect medians of 2.5 x 10(8) mononuclear cells per kg (range, 1.0-7.4), 14 x 10(4) CFU-GM per kg (0-208), 27 x 10(4) clonogenic progenitor cells per kg (0-370), and 2.8 x 10(6) CD34+ cells per kg (0-112.5). Fifty-seven percent of patients (8/14) required one or two LVL procedures to collect adequate blood progenitor cells (range, 1-4). After dose-intensive chemotherapy, 13 patients received medians of 6.8 x 10(8) mononuclear cells per kg (range, 5.1-9.9), 53 x 10(4) CFU-GM per kg (9-208), and 12 x 10(6) CD34+ cells per kg (3.6-112.5). Rapid hematopoietic reconstitution occurred with 10 days (range, 8-12) and 9 days (6-15), respectively, for neutrophil and platelet recoveries. CONCLUSION: Scheduled LVL, beginning on Day 14 after the administration of granulocyte-macrophage-colony-stimulating factor following chemotherapy, is a convenient and efficient method of collecting blood progenitor cells. The mononuclear cells so obtained effected consistent and rapid hematopoietic reconstitution in a highly reproducible manner in a group of heavily treated patients.

Treatment of malignant pleural mesothelioma with cisplatin, mitomycin C and alpha interferon.

From October 1990 to September 1991, 20 consecutive patients with histologically proven malignant pleural mesothelioma (MPM), secondary to environmental exposure to asbestos or erionite, were treated with cisplatin, mitomycin C and alpha interferon (cisplatin 50 mg/m2 i.v. on day 1 of a 21-day cycle; mitomycin C 10 mg/m2 i.v. day 1 of cycles 1,3 and 5; alpha-2b-interferon 10 x 10(6) units i.m., 4 h prior to cisplatin and 10 x 10(6) units i.v. immediately prior to cisplatin day 1 of each cycle). Eighty-two treatment cycles were administered to 19 evaluable patients. Two patients attained a partial response. Eleven patients had stable disease and 6 had disease progression. Toxicities included interferon-related fever and flu-like symptoms, and vomiting. Actuarial median survival was 15 months. Three patients are alive at 20+, 21+ and 27+ months. We conclude that while the addition of alpha interferon to cisplatin and mitomycin C did not result in an objective response higher than previously reported with the cytotoxic agents alone, the trend towards an improvement in median survival as compared to a well-matched historical group suggests some benefit from the inclusion of interferon.

Treatment of advanced non-small cell lung cancer with very high-dose cisplatin combined with etoposide and mitomycin C.

BACKGROUND: Treatment options for advanced non-small-cell lung cancer are inadequate. There remains a critical need for more effective systemic therapies. METHODS: Forty-one patients with advanced non-small-cell lung cancer were treated on a 28-day cycle with a very high-dose, cisplatin-based three-drug regimen. A treatment cycle consisted of an intravenous (IV) injection of cisplatin 100 mg/m2 on days 1 and 8; etoposide 60 mg/m2 IV over 30 minutes on days 1, 2, 8, and 9 (cycles 1 and 3 only); and mitomycin C 8 mg/m2 IV bolus on day 1 (cycles 2 and 4 only) (PEM regimen). RESULTS: The median dose intensity of cisplatin delivered was 49 mg/m2/wk, or 98% of the planned dose. One patient achieved a complete response and 16 patients a partial response or regression, yielding an overall objective response rate of 41%. The median duration of response was 21 weeks. Median survival of all patients was 38 weeks. Neurologic toxicity was dose limiting. The frequency of peripheral neuropathy and ototoxicity was directly related to cumulative cisplatin dose. In five patients, a progressive peripheral neuropathy developed after discontinuation of cisplatin. Hematologic toxicity also was significant. CONCLUSIONS: This very high-dose, cisplatin-based chemotherapy regimen has appreciable activity in advanced non-small-cell lung cancer. In comparison with previous reports on the use of very high-dose cisplatin alone, however, this combination appears at best to be only marginally more active, to confer no additional survival advantage, and to be considerably more toxic.