Drug control of Ara-C-resistant tumor cells.

Abstract

1-β-D-Arabinofuranosylcytosine (Ara-C) is an important component of a number of clinically useful but usually not curative drug combinations used to treat acute myeloid leukemia of adults. It has marked activity against high growth fraction murine leukemias, including L1210 and P388. Extensive trials with Ara-C treatment of mice with large body burdens of L1210 or P388 and a markedly sensitive transplantable colon carcinoma of mice (colon 36) have consistently shown that failure to cure these tumors by treatment with Ara-C is due to the overgrowth of Ara-C-resistant tumor cells. L1210 and P388 cells that are resistant to Ara-C retain essentially unchanged sensitivity to representatives of all of the other major chemical and functional classes of clinically useful anticancer agents including alkylating agents, drugs that bind to or intercalate with DNA, other classes of antimetabolites, and mitotic inhibitors. Experimental data show that marked therapeutic improvement (including many cures) can be obtained on treating mice bearing large body burdens of L1210 or P388 cells by simultaneous, alternating, or sequential delivery of Ara-C plus other non-cross-resistant drugs. A number of other anticancer drugs, which are also inhibitors of de novo pyrimidine synthesis [5-fluorouracil (5-FU), 3-deazauridine, dihydro-5-azacyti-dine, N-(phosphonacety1)-L-aspartate (PALA), and pyrazofurin] have been shown to be orders of magnitude more cytotoxic in vivo against Ara-C-resistant L1210 and/or P388 cells (collateral sensitivity) than against Ara-C-sensitive L1210 and/or P388 cells. Marked therapeutic synergism has been shown against advanced P388 by the combination of palmO-Ara-C (the 5′-palmitate of Ara-C) plus PALA. The tumor was sufficiently advanced at start of drug treatment that treatment with palmO-Ara-C alone failed, due to overgrowth of Ara-C-resistant tumor cells present at start of therapy. The addition of PALA, in itself not effective against Ara-C-sensitive P388 but markedly cytotoxic for Ara-C-resistant P388, resulted in kill of most, if not all, of the Ara-C-resistant cells. Similar trials against advanced L1210 with palm0-Ara-C plus 3-deazauridine (a drug to which Ara-C-resistant L1210 cells show collateral sensitivity) have failed to show improved therapeutic response, presumably due to increased toxicity of the drug combination for vital normal cells. Ara-C plus 5-W, dihydro-5-azacytidine, or pyrazofurin have not yet been studied. Therapeutic synergism between palmO-Ara-C and dihydroxyanthracenedione (DiOHA), including many cures, was shown against body burdens of > l08 P388 cells in mice. Body burdens of tumor cells of this magnitude assured failure to cure with palmO-Ara-C or DiOHA when used alone. The fact that Ara-C resistant L1210 was cross-resistant to 2-fluoro-9-P-D-ara- binofuranosyladenine (2-F-Ara-A) in vivo led to studies which indicated that 2-F-Ara-A is phosphorylated to its 5′-monophosphate by deoxycytidine kinase, thus explaining the cross-resistance of Ara-C-resistant L1210 to treatment with 2-F-Ara-A. Basic information gained on the biochemical basis of cellular resistance to Ara-C (and the cross-resistance and lack of cross-resistance of Ara-C-resistant neoplastic cells to other drugs) and observations that Ara-C-resistant cells are collaterally sensitive to certain other agents seems to provide the background for design of future chemotherapeutic regimens.