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In Vitro Pharmacodynamics of 1-ß-D-Arabinofuranosylcytosine: Synergy of Antitumor Activity with cis-Diamminedichloroplatinum(II)¹

Research Service, Veterans Administration Medical Center, Sepulveda, California 91343, and Division of Surgical Oncology, John Wayne Clinic, Jonsson Comprehensive Cancer Center, UCLA School of Medicine, Los Angeles, California 90024

1-ß-D-Arabinofuranosylcytosine (ara-C) was tested at a concentration of 10 µg/ml in the human tumor colony-forming assay against 55 human tumors of various histological types. Using the criterion for sensitivity of at least 70% inhibition of colony formation, 12 tumors (22%) were sensitive to ara-C. ara-C was most active against lung tumors (3 of 8 tumors were sensitive), and melanomas (6 of 8 sensitive). However, ara-C was not active against breast cancer (0 of 7) or colon cancer (0 of 3), and only 1 of 13 ovarian cancers was sensitive to ara-C. The activity of ara-C against melanoma and other solid tumors was confirmed using a thymidine incorporation assay. The time (t) and concentration (C) dependency of the cytotoxicity of ara-C and other chemotherapeutic agents was determined. Most agents such as Adriamycin, cis-diamminedichloroplatinum(II) (cis-platinum), and bleomycin were found to follow the C x t rule. That is, as the drug concentration was doubled, an equivalent amount of cell kill was achieved in half the time. However, the activity of ara-C was more concentration dependent than time dependent. ara-C was more effective when cells were exposed to high concentrations for short time periods. Synergy of activity between ara-C and cis-platinum was demonstrated in the breast 231 and melanoma M19 cell lines. No synergy of interaction between these two drugs was observed in the colon HT29 and lung P3 cell lines. When fresh biopsy specimens were tested with the combination, there was evidence of a synergistic interaction in 9 of 36 (25%). Maximum cytotoxicity was obtained when cells were exposed to ara-C 2 h before the addition of cis-platinum. The addition of cis-platinum before ara-C decreased the synergism.

¹ This work was supported in part by a gift from The Upjohn Company and the Veterans Administration Medical Research Service.

Received 5/22/87. Revised 8/25/87. Accepted 10/ 7/87.

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