Cytotoxicity of combinations of prostaglandin D2 (PGD2) and antitumor drugs for B16 melanoma cells in culture.

Prostaglandin D2 (PGD2) is lethal to murine and human melanoma cells at high doses, but synchronizes cells at G1 at non-toxic doses (2.5 or 5 micrograms/ml). We tested the lethality to B16 mouse melanoma cells of combinations of PGD2 with anticancer drugs. The drugs selected were mostly those used in treating human melanoma: actinomycin D, Bleomycin, BCNU, cis-platin, melphalan, 5-fluorouracil, and 1-beta-D-arabinofuranosylcytosine (ara-C). PGD2 was combined with the drugs according to 3 different protocols: An asynchronous culture was given a long term (24 hr) exposure simultaneously to PGD2 + drug. Combinations with Bleomycin, ara-C or melphalan were additive or slightly antagonistic whereas PGD2 plus actinomycin D was significantly antagonistic. Cells synchronized in G1 by 24 hr PGD2 exposure were then given a short-term (2 hr) treatment with PGD2 + drug. Combinations with cis-platin, Bleomycin, BCNU or 5-fluorouracil were additive or slightly antagonistic, whereas melphalan and actinomycin D combinations were significantly antagonistic. Cells were released from a PGD2-induced G1 block and were exposed to drug at different times during cell progression. Actinomycin D was antagonistic when added immediately after release from the G1 block, but was significantly synergistic when added 10 to 12 hr later. The effect of the combinations cannot be explained by available cell cycle or biochemical information. The antagonism between PGD2 and several of the drugs resembles the "cytoprotective" effect of PGD2 towards various noxious agents.