BIOCHEMICAL PHARMACOLOGY OF NEW ANTHRACYCLINES

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The proposed research is directed toward determining the chemical, biochemical, and cellular basis for the extremely potent antitumor activity of the sugar-modified analog of doxorubicin (DXR), cyanomorpholinyl doxorubicin (CM-DXR), which is 100 to 1000 times more potent than DXR in vitro and in vivo in animal tumors and in vitro in human tumor cells in the absence of cardiotoxic effects in animal test system. It is also noncross- resistant to DXR-resistant tumor cells in vitro. The pivotal chemical event is proposed to be that the cyano group of CM-DXR leaves the molecule, resulting in an minimum alkylating species of extremely high potency. That the non- cyano-containing morpholinyl DXR (M-DXR) requires metabolic activation by mammalian systems to yield activities similar to CM-DXR supports the minimum postulate. Also, we have recently demonstrated surprisingly facile and rapid exchange of the cyano group of CM-DXR with 14CN- in aqueous systems at pH 7.3. We propose to study these mechanisms by an integrated chemical and biochemical approach. The chemical approach will be to synthesize directly cyanomorpholinyl and oxygen-bridged morpholinyl derivatives of DXR and daunorubicin (DNR) for testing in P388 cells, both sensitive (S) and resistant (R) to DXR. The biochemical approach will be to test the hypothesis that morpholinyl derivatives are alpha-hydroxylated by liver microsomal enzymes. Associated with these studies will be assessments of the role of DNA-adduct formation, via 32P- postlabeling techniques, in the sensitivity of P388/S and P388/R cells to DXR, M-DXR, CM-DXR, similar DNR analogs, and other compounds in the mice. Finally, we will test the most active, stable, promising new compounds in mice against P388 tumor cells. Combined with these later tests will be determinations of the metabolic disposition of the new compounds.