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In Vitro Sensitivity to Steroid Hormones and Cytotoxic Agents of Normal and Malignant Lymphocyte Colony-forming Cells¹

Departments of Medicine [R. T., D. T., J. M.] and Pathology [R. T.], University of California Medical Center, San Diego, California 92103

In vitro assays were used to assess the sensitivity of normal T-cells and malignant, chronic lymphocytic leukemia (CLL) lymphocyte colony-forming cells (CFC) to a panel of cytotoxic drugs and steroid hormones. Normal T-CFC were remarkably resistant to hydrocortisone, progesterone, estradiol, and testosterone at concentrations 10^-5 M. Variable inhibition was seen at concentrations of 10^-4 M, and prior exposure to phytohemagglutinin increased sensitivity only to sex steroid hormones. In contrast to T-CFC, which showed little variation in patterns of steroid hormone inhibition in vitro, CLL-CFC from individual patients displayed widely varying sensitivity to all hormones tested; 50% inhibitory dose varied by as much as 2 logs. T-CFC were fairly resistant to a 1-hr exposure to achievable concentrations of 1-ß-D-arabinofuranosyl-cytosine, 5-fluorouracil, chlorambucil, melphalan, cisplatin, methotrexate, Adriamycin, and bleomycin. Prior exposure to phytohemagglutinin resulted in increased sensitivity only to low concentrations of Adriamycin, a phenomenon that appeared related to prior or concurrent lectin exposure and not to changes in cell cycle status. CLL-CFC showed variable sensitivity to Adriamycin and cisplatin, and concurrent exposure to lectin and Adriamycin did not increase sensitivity to that drug. CLL cells displayed much greater sensitivity to a 1-hr exposure to antimetabolites and bleomycin than to continuous exposure to the same drugs. In contrast to normal T-CFC, CLL-CFC exposed to methotrexate were not "rescued" by subsequent culture in media and fetal bovine serum. Incubation of T-CFC or CLL-CFC with melphalan and a source of protein (fetal bovine serum or bovine serum albumin) resulted in decreased cell kill. Differences in in vitro sensitivity of normal and malignant lymphocyte CFC to steroids and cytotoxic agents can be demonstrated using these culture systems. CLL-CFC showed variable sensitivity to hydrocortisone, and much greater sensitivity to antimetabolites than normal T-CFC. Differences in conditions of drug exposure, such as concurrent exposure to lectin or inclusion of protein, may alter the in vitro sensitivity of lymphocyte CFC to some drugs.

¹ This investigation was supported in part by American Cancer Society RD136 and CH230, and USPHS CA 23100 awarded by the National Cancer Institute, Department of Health and Human Services.

² Junior Faculty Clinical Fellow (No. 583) of the American Cancer Society, Dr. Mendelsohn is a Professor of Clinical Oncology, American Cancer Society. To whom requests for reprints should be addressed, at University Hospital H720, 225 Dickinson Street, San Diego, Calif. 92103-9981.

Received 1/24/83. Accepted 4/28/83.