THE EFFECT OF SODIUM-BUTYRATE, INTERFERON-ALPHA AND VERAPAMIL ON THE SENSITIVITY OF OVARIAN-CARCINOMA CELLS TO ADRIAMYCIN

Background - Acquired drug resistance and drug toxicity are the main limitations to successful chemotherapy. The addition of modifiers is intended to increase drug sensitivity and to decrease systemic toxicity. Modulation of the sensitivity of ovarian tumor cells to adriamycin by sodium butyrate, interferon-alpha and verapamil was investigated. Methods - First passage cultures of cells derived from the ascitic fluid a clinically refractory ovarian carcinoma patient (BH) and an established ovarian tumor cell line (CAOV-3) were used. Chromosomal G-banding, lipid content and alkaline phosphatase activity were investigated. CA 125 and P-glycoprotein were shown by immunoperoxidase staining. P-glycoprotein function was demonstrated using rhodamine. Drug sensitivity was determined by the MTT method. Results - Double minute chromosomes and a homogeneously staining region were found in BH cells. CAOV-3 and BH were CA 125-positive. Most of BH and several CAOV-3 cells were P-glycoprotein-positive. The P-glycoprotein-transport system was active in BH and less so in CAOV-3 cells. Sodium butyrate increased lipid accumulation whereas interferon-alpha decreased alkaline phosphatase activity in CAOV-3 (50%). CAOV-3 were initially more sensitive to adriamycin than BH. Sodium butyrate potentiated the antiproliferative effect of low concentrations of adriamycin in BH while in CAOV-3 the effect was less pronounced. BH and CAOV-3 cells showed different sensitivity profiles to interferon-alpha. Addition of interferon to adriamycin resulted in an additive growth inhibiting effect in BH cells only. Verapamil, known to reverse multidrug resistance, potentiated the antiproliferative activity of adriamycin in BH, whereas in CAOV-3 its effect seemed additive. Conclusions - Our results may suggest a possible advantage in using a combination of adriamycin and sodium butyrate in clinical trials since sodium butyrate, in contrast to verapamil, is practically non-toxic.