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 g/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--D-arabinofuranosylcytosine (ara-C). PGD₂ was combined with the drugs according to 3 different protocols:Protocol 1 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.Protocol 2 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.Protocol 3 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.