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Studies on the Mechanism of Resistance to Lymphocytolysis Induced by Corticosteroids¹

Department of Biochemistry, University of British Columbia, Vancouver 8, Canada

Isolated nuclei from thymus, corticosteroid-sensitive, and -resistant mouse lymphosarcoma P1798 were unaffected after 5 hr of incubation with 2.7 µM cortisol, but all underwent degenerative changes when exposed to 50 µM free fatty acid. In intact sensitive cells, free fatty acid (FFA) decreased the uptake of thymidine but did not mimic the other inhibitory effects of cortisol on uptake of deoxyglucose, leucine, or uridine. Resistant cells have less than one-half (12.9 mg/g) the neutral fat content of the sensitive line (29.9 mg/g) and one-quarter of that reported for thymus. The capacity of three resistant tumor lines, P1798R, L1210, and L5178Y, for FFA oxidation was diminished by 0.5 mM deoxycarnitine or 132 µM citral with some cytolysis. The effects of citral increased with concentration, causing complete lysis at 330 µM or at 132 µM when combined with 80 µM FFA. The data support the mechanism proposed earlier that cytolysis results from accumulation of FFA which damages primarily the nucleus, and resistance is attributable mainly to the capacity for FFA oxidation, the impairment of which can result in lysis of resistant cells.

¹ This investigation was supported by a grant from the Medical Research Council of Canada. Preliminary reports of this study were presented at the 62nd and 63rd Annual Meetings of the American Association of Cancer Research, Chicago, Ill. (1971) and Boston, Mass (1972).

² The studies reported are from a thesis submitted to the University of British Columbia in partial fulfillment of the requirements for the degree of Doctor of Philosophy. Recipient of a Medical Research Council Studentship. Present address: Department of Biochemistry, University of Rochester Medical Center, Rochester, N. Y. 14642.

Received 5/ 4/73. Accepted 9/21/73.