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Preclinical Antitumor Activity of an -Picoline Derivative, Penclomedine (NSC 338720), on Human and Murine Tumors¹

Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute, Bethesda, Maryland 20892 [J. P., K. D. P., V. L. N.]; Southern Research Institute, Birmingham, Alabama 35255 [S. D. H., D. J. D., D. P. G.]; Dow Chemical USA, Walnut Creek, California 94598 [H. K. T.]; and Merrell Dow Research Institute, Indianapolis, Indiana 46268 [J. M.]

Penclomedine, a synthetic -picoline derivative, was identified as a potential antitumor agent in the P388 leukemia prescreen of the National Cancer Institute. Upon further evaluation in the National Cancer Institute in vivo tumor panel, the compound demonstrated good activity against two breast tumors. A single i.p. dose or five daily doses caused partial regressions of advanced-stage s.c. implanted mouse CD8F₁ mammary adenocarcinomas. Also, penclomedine administered i.p. on Days 1, 5, and 9 caused regression of the human MX-1 mammary carcinoma implanted under the renal capsule of athymic mice. In contrast, penclomedine demonstrated only marginal to moderate activity against the i.p. implanted L1210 leukemia and M5076 sarcoma and was inactive in three additional non-breast tumor models (i.p. B16 melanoma, i.v. Lewis lung carcinoma, and s.c. colon adenocarcinoma 38). Penclomedine administered p.o. and i.p. was equally effective against the subrenal capsule MX-1. Doses given p.o. every fourth day caused complete regression of 39 of 40 advanced-stage s.c. implanted MX-1 tumors but were much less effective against human H82 small cell lung carcinomas (13 of 80 complete regressions). Penclomedine p.o. also inhibited growth of the human MCF-7 and mouse 16/C breast adenocarcinomas. Further studies to support the development of penclomedine to clinical trial are in progress.

¹ This investigation was supported in part by Contract N01-CM7-3726 from the Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute, Department of Health and Human Services.

² To whom requests for reprints should be addressed.

Received 9/ 6/88. Revised 1/ 4/89. Accepted 1/11/89.

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