Therapeutic Synergism of Hyperthermia-cis-Platinum in a Mouse Tumor Model23

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Abstract
A small-animal model was developed as a guide to whole-body hyperthermia in cancer patients. Anesthetized DBA/2 mice were secured to a platform, and their hindlimbs were immersed in a 42.3° C water bath for 30–60 minutes. Hindlimb hyperthermia resulted in steady-state rectal and femoral bone marrow and muscle temperatures of 42° C and upper extremity muscle and esophagus temperatures of 41° C. With this hyperthermia technique, the mouse spleen colony assay could be used to quantitate the lethality of hyperthermia and/or cis-dichlorodiammineplatinum(II) (cis-platinum) on clonogenic bone marrow and leukemia cells. Hyperthermia prior to cis-platinum administration increased cis-platinum inhibition of leukemia colony formation as much as 2 logs; however, antileukemia synergism was greatest when cis-platinum administration immediately preceded hyperthermia and no evidence existed of synergism against normal bone marrow colonies. Correlative in vivo drug uptake studies showed a marked increase in leukemia cell uptake of 195mPt-cis-platinum at elevated temperatures, which suggested a potential mechanism for the apparent antileukemia synergism of cis-platinum and heat.