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¹²-Prostaglandin-J₂ Is Cytotoxic in Human Malignancies and Synergizes with Both Cisplatin and Radiation¹

Division of Hematology/Oncology, Department of Medicine [E. F. M., P. J. W., J. A. J.], and Department of Radiation Oncology [J. J. III. S. G-C.], Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina 20403

We have been investigating the synergistic cytotoxic interactions between tamoxifen (TAM) and cisplatin (DDP) in human malignant cell lines. Recent data have demonstrated that TAM activates phospholipase D, which can increase the production of prostaglandin D₂. Prostaglandin D₂ has been shown to have growth inhibitory properties in several malignant cell lines. ¹²-Prostaglandin-J₂ (¹²-PG J₂) is a derivative of prostaglandin D₂ that has been shown to have similar inhibitory properties. We hypothesized that TAM may increase the production of ¹²-PG J₂, which in turn may synergize with DDP. To begin our investigation of this interaction, we sought to determine if ¹²-PG J₂ was cytotoxic and synergistic in our melanoma system and then expanded our observations to include a wide range of malignant cells. We have demonstrated that ¹²-PG J₂ is cytotoxic to multiple malignant cell lines including melanoma, ovarian, prostate, colon, pancreas, small cell lung cancer, and breast cancer lines. The IC₅₀s ranged from 0.70 µM (small cell lung cancer) to 3.30 µM (DDP-resistant melanoma). Additionally, ¹²-PG J₂ exhibited synergistic cytotoxicity with both DDP and ionizing radiation. These data suggest that ¹²-PG J₂ should be further evaluated in an in vivo model to confirm activity.

¹ Supported by Grant CA-51251 from the NIH.

² To whom requests for reprints should be addressed, at Hollings Cancer Center, 86 Jonathan-Lucas Street, Room 315, Charleston, SC 29403.

Received 5/ 6/96. Accepted 7/17/96.

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