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Cytotoxic Interactions of Heat and an Ether Lipid Analogue in Human Ovarian Carcinoma Cells¹

Departments of Radiology [K. F., C. A. W.], Biochemistry [E. J. M.], and Obstetrics and Gynecology [C. E. W.], Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, North Carolina 27103

Ether lipid (EL) analogues of platelet activating factor are known to have a cell membrane-mediated antitumor activity. Although previous studies demonstrated additive interactions with EL and conventional DNA-interacting chemotherapeutic agents, little is known about the interaction of EL with heat. In this study, the cytotoxic interaction of one EL analogue, ET-18-OMe, with heat was measured at two different temperatures, 42 and 44°C, using BG-1 human ovarian carcinoma cells. When the number of colonies, 40 µm in diameter, was counted as a function of incubation time, the rate of colony formation was suppressed by treatment with ET-18-OMe alone at doses 2.0 µM or with heat alone. The combination of ET-18-OMe with heat inhibited the colony formation of the slowest growing fraction of the heated cells. The dose-response curve for BG-1 cells after continuous exposure to ET-18-OMe alone was exponential with a small shoulder (D_q = 0.25 µM). The T₀ value (the time to reduce survival on the exponential portion of the curve by a factor of 1/e) of the 44°C dose-response curve (30 min) was reduced to half (15 min) by the addition of 0.25 to 1.0 µM ET-18-OMe, but increased again to 24 min when heat was combined with ET-18-OMe concentrations 2.0 µM. The thermotolerant tail seen in the dose-response curve after continuous heating at 42°C was removed by adding as little as 0.25 µM ET-18-OMe. Isobologram analysis for the combined treatments with 44°C heat and ET-18-OMe at surviving fractions of 0.5, 0.3, 0.1, and 0.01 showed that the treatments were supraadditive at low concentrations (<0.5 µM) of ET-18-OMe and additive at moderate concentrations (0.5 to 1.0 µM) of ET-18-OMe. Similarly, the interaction of ET-18-OMe with 42°C heat at surviving fractions of 0.3 and 0.1 was supraadditive at low concentrations (<0.5 µM) of the ET-18-OMe and additive with moderate concentrations (0.5 to 1.5 µM) of ET-18-OMe. Because the greatest interaction of ET-18-OMe and heat occurred at clinically achievable doses of both agents, this combination of agents should be considered for use in clinical trials.

¹ Supported by NIH Grant CA 44105 from the National Cancer Institute.

² To whom requests for reprints should be addressed, at Department of Radiology, Bowman Gray School of Medicine, 300 South Hawthorne Road, Winston-Salem, NC 27103.

Received 5/16/89. Revised 8/15/89. Accepted 8/22/89.