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The Prediction of Growth-inhibitory Drug Combinations Showing Enhanced Differential Toxicity and Collateral Sensitivity

( Department of Experimental Biology, Roswell Park Memorial Institute, Buffalo, New York)

The possible application to chemotherapy of factors affecting the regulatory systems of cells has been considered. The extensive coordinate changes in intracellular enzyme concentrations which result from exposure to compounds interfering with the normal regulatory mechanisms suggest the possibility of combination therapy based upon the selective induction of quantitative changes in enzymatic activities. Such approaches would appear to be useful in circumventing two major problems of chemotherapy: finding sufficient metabolic differences between host and parasite to provide targets for selective drug toxicity, and preventing the eventual development of drug resistance.

It is concluded that a combination of two compounds affecting the same metabolic pathway, one producing feedback inhibition and the other effective through lethal synthesis, will show an enhanced differential toxicity greater than that from either drug alone. Similarly, pairs of compounds in which one member produces enzyme repression and the other is active through lethal synthesis should produce collateral sensitivity and thus prevent the development of drug-resistant populations.

Received 5/25/62.