We found that human malignant melanoma cells had varying thermal sensitivity and that some exhibited natural thermal resistance, a heretofore unrecognized phenomenon. Samples of 73 melanoma cell suspensions were heated at 42 degrees C for 1 hour before plating in the soft agar clonogenic assay or the thymidine assay for proliferating cells. We observed greater than 75% cell kill after hyperthermia in 39 (53%) tumors. Native thermal resistance was apparent in 17 (23%) tumors and growth enhancement in 17 (23%) at this temperature and exposure time. We postulated that prostaglandin, known to protect stomach mucosa against thermal injury, has a role in stabilizing the tumor cell membrane exposed to heat. Three melanoma cell lines known to be thermosensitive were heated to 42 degrees C without and with exogenous prostaglandin E2 (PGE2). The survival of colony-forming cells was increased in all three lines in the presence of 30 microM PGE2. A naturally thermoresistant cell line was exposed to 1 microgram/ml indomethacin for 24 hours before hyperthermic treatment. The survival of colony-forming cells was significantly decreased compared to cells not treated with indomethacin. The addition of 30 microM of exogenous PGE2 to indomethacin-treated cells reestablished thermal resistance. These preliminary data suggest that some tumor cells synthesize prostaglandins to render the cell thermoresistant. Treatment with indomethacin blocks prostaglandin synthesis and induces thermosensitivity. These discoveries may have important clinical applications for hyperthermia treatment of human cancers.