Combination effects of cisplatin, vinorelbine and irinotecan in non-small-cell lung cancer cell lines in vitro.

PURPOSE: Isobologram analysis has been widely used for evaluating the combined effect of two antitumor drugs in vitro as a pre-clinical screening test. In this study, we tried to extend two-dimensional isobologram analysis to three dimensions for evaluating the effects of a three-drug combination. METHODS: We selected three anticancer agents, cisplatin, vinorelbine and irinotecan. Each of them has been classified as having good single-agent activity against non-small-cell lung cancer (NSCLC). Human NSCLC cell lines (EBC-1, PC-3, RERF-LC-MS) were incubated for 4 days in the presence of the three drugs and cytotoxic activities were determined by a tetrazolium-based colorimetric assay (MTT assay). The data were analyzed by three dimensional isobologram analysis. RESULTS: The effects of the three drugs were additive against EBC-1 (a squamous cell carcinoma cell line), subadditive against PC-3 (an adenocarcinoma cell line) and from subadditive to supraadditive against RERF-LC-MS (an adenocarcinoma cell line). CONCLUSIONS: Our findings suggest that the effects of cisplatin, vinorelbine and irinotecan in combination are additive against NSCLC in vitro. These results encourage clinical trials of the three agents in combination chemotherapy for the treatment of NSCLC.

Stimulation of acyl-CoA:cholesterol acyltransferase activity by brefeldin A in macrophage J774 cells.

Brefeldin A (BFA), an inhibitor of secretory pathway, enhances incorporation of radiolabeled cholesterol and oleate into cholesteryl esters in cultured cells [12]. We studied the mechanism for this effect of BFA in the macrophage J774. When incubated with 2.7 microM BFA in the absence of lipoproteins, J774 cells synthesized and accumulated 1.5- to 4-fold more cholesteryl esters than did cells which received no BFA. BFA caused neither an elevation of cholesterol synthesis, inhibition of its secretion nor changes in cholesterol transport to plasma membrane, esterification of plasma membrane cholesterol and cholesteryl ester hydrolysis. Acyl-CoA:cholesterol acyltransferase (ACAT) activity in microsomes from BFA-treated cells was 1.5- to 1.8-fold higher than that from control cells. The effect of BFA was diminished by treatment with low temperature, which is known to abolish BFA effect on Golgi formation.

[Combination chemotherapy with cyclophosphamide, adriamycin, cisplatin, nimustine, and methotrexate (EACAM) in advanced adenocarcinoma of the lung].

Twenty-eight patients with advanced adenocarcinoma of the lung were treated with the combination chemotherapy "EACAM" consisting of cyclophosphamide (333 mg/m2 X 1), adriamycin (27 mg/m2 X 1), cisplatin (25 mg X 5), nimustine (33 mg/m2 X 1), and methotrexate (27 mg/m2 X 3). This regimen was repeated once every 4 or 5 weeks. One complete response (CR) and 10 partial responses (PR) were obtained in 27 evaluable patients and the response rate was 40.7%. The 50% survival time for all of the evaluable cases was 64 weeks. The 50% survival time for the responding patients (93 weeks) was significantly superior (p = 0.002) to that of the nonresponding patients (52 weeks). Alopecia, myelosuppression and mild G I trouble were observed, but these presented no obstacle to the continuation of the therapy. The combination chemotherapy "EACAM" is therefore considered to be a very effective and tolerable treatment for advanced adenocarcinoma of the lung, and can help in achieving our aim of prolonging the survival time of such patients.

K-582, a new peptide antibiotic. I.

A new basic peptide antibiotic designated as K-582 was isolated, purified and characterized. When K-582 was applied to a column of Al2O3 or Biol-Gel P-2 or CM Sephadex, two major peaks which were named Fraction I (K-582 A) and Fraction II (K-582 B) were obtained. The nitrogen content, the behavior in color reaction, the absorption bands of amide linkages in the infrared absorption spectrum, 1H NMR spectrum and C-13 NMR spectrum indicated the peptide nature of K-582 A and K-582 B. K-582 was effective against yeasts, but inactive against other Gram-positive bacteria, Gram-negative bacteria and Mycobacterium. The toxicity was low in mice.