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Response of Drug-sensitive and -resistant L1210 Leukemias to High-Dose Chemotherapy¹

Southern Research Institute, Birmingham, Alabama 35255-5305 [D. P.G., M. W. T., W. R. L.]; Dana-Farber Cancer Institute, Boston, Massachusetts 02115 [E. F.]; Duke University Medical Center, Bone Marrow Transplant Program, Durham, North Carolina 27710 [W. P. P.]; and Division of Cancer Treatment, National Cancer Institute, Bethesda, Maryland 20892 [M. K. W.]

Alkylating agent-sensitive and -resistant L1210 leukemia cell lines were used to determine the tumor response to dose levels of drugs that exceeded conventional doses up to a factor of 10. Since those dose levels were lethal to the host mice, tumor response was based on the results of in vivo bioassays of spleen and/or tumor from drug-treated and control mice. When mice bearing about 10⁸ drug-sensitive leukemic cells were treated with a single, conventional (approximately 10% lethal) dose of cis-diamminedichloroplatinum, L-phenylalanine mustard (melphalan), or 1,3-bis(2-chloroethyl)-1-nitrosourea, 10¹ to 10⁴ tumor cells were recovered by bioassay. Treatment at doses that were 2 to 8 times the 10% lethal dose of either of those drugs resulted in no recoverable cells and survival of all bioassay recipient mice. Mice bearing advanced L1210 leukemia resistant to cis-diamminedichloroplatinum (L1210/DDPt), 1,3-bis-(2-chloroethyl)-1-nitrosourea (L1210/BCNU), cyclophosphamide_(L1210/CPA), or melphalan_{(L1210/L-PAM)} also were treated with a 10% lethal dose and greater doses of the drug to which the tumor line was resistant. Bioassay results indicated a direct correlation between dose intensity and tumor cell kill, the response being linear. Similarly, when mice with L1210/BCNU were treated with high doses of N-(2-chloroethyl)-N'-(2,6-dioxo-3-piperidinyl)-N-nitrosourea or 1,1',1''-phosphinothioylidynetrisaziridine (thioTEPA) and when mice with L1210/DDPt were treated with cyclophosphamide, an increasing, linear cell kill resulted throughout the high-dose range. Overall, these results indicate that resistance to these alkylating agents can be overcome by dose intensification and that the tumor response is linear in relation to increasing dose level.

¹ This work was supported in part by National Cancer Institute Grant 1PO1-CA-34183 and by National Cancer Institute Contract NO1-CM-47580. Part of the work was presented at the 76th Annual Meeting of the American Association for Cancer Research, May 22 to 25, 1985, Houston, TX.

² To whom requests for reprints should be addressed, at Southern Research Institute, P. O. Box 5305, Birmingham, AL 35255-5305.

³ Deceased.

Received 11/20/86. Revised 2/ 5/87. Accepted 2/ 9/87.