CYTOTOXIC INTERACTIONS OF TUMOR-NECROSIS-FACTOR, MELPHALAN AND 41.8-DEGREES-C HYPERTHERMIA

Experience with limb perfusion-hyperthermia, TNF, and L-PAM suggests d ramatic clinical responses in sarcoma and malignant melanoma. To extra polate these results to clinical 41.8 degrees C whole-body hyperthermi a (WBH) and systemic therapy, we studied the cytotoxic interactions of TNF, L-PAM and hyperthermia in L929 cells. The optimal sequence was T NF preceding 41.8 degrees C hyperthermia by 48 h, and L-PAM given simu ltaneously with heat. Trimodality synergism between TNF, hyperthermia and L-PAM was demonstrated. Non-cytotoxic doses of TNF had a superaddi tive interaction with L-PAM/heat. Conversely, non-cytotoxic doses of L -PAM had super-additive interactions with TNF followed by hyperthermia . Relative to therapeutic index, we studied WBH, L-PAM and TNF in non- tumor bearing mice. The optimal trimodality sequence did not result in increased normal tissue toxicity compared to L-PAM alone, The concent rations and sequencing of TNF and L-PAM studied are consistent with cl inical application to WBH.