This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wadkins, R. M. Articles by Von Hoff, D. D. Search for Related Content PubMed PubMed Citation Articles by Wadkins, R. M. Articles by Von Hoff, D. D.

Hydrophilic Camptothecin Analogs That Form Extremely Stable Cleavable Complexes with DNA and Topoisomerase I

¹ Department of Chemistry and Biochemistry, University of Mississippi, University, Mississippi; ² Research Triangle Institute, Research Triangle Park, North Carolina; and ³ University of Arizona Cancer Center, Tucson, Arizona

Camptothecin (CPT) analogs that form more stable ternary complexes with DNA and topoisomerase I (termed cleavable complexes) show greater activity in their ability to inhibit tumor cell line growth in preclinical studies. Based on our earlier work, we hypothesized that analogs bearing hydrogen bonding moieties at the 7- through 10-position of CPT would result in more stable cleavable complexes. Consequently, we synthesized analogs with 7-mono-, 7-di-, and 7-trihydroxymethylaminomethyl groups. These analogs showed increasing cleavable complex stability as the number of hydroxyl groups was increased. The 7-trihydroxymethylaminomethyl analog of 10,11-methylenedioxycamptothecin (THMAM-MD) showed remarkable ternary complex stability with a half-life of 116 minutes. This is an order of magnitude more stable than any previously examined analog. Our in vitro analysis demonstrated that these analogs were all potent topoisomerase I poisons and could inhibit tumor cell growth in culture. We studied the effects of THMAM-MD in vivo in severe combined immunodeficient mice bearing HT-29 colon cancer and MiaPaCa-2 pancreatic cancer tumors. The THMAM-MD analog showed excellent, persisting activity in inhibiting tumor growth with both lines. Taken together, our results suggest that CPTs with hydrophilic, hydrogen-bonding groups at the 7-position hold the promise of excellent clinical activity.

This article has been cited by other articles:

				C. Pisano, M. De Cesare, G. L. Beretta, V. Zuco, G. Pratesi, S. Penco, L. Vesci, R. Fodera, F. F. Ferrara, M. B. Guglielmi, et al. Preclinical profile of antitumor activity of a novel hydrophilic camptothecin, ST1968 Mol. Cancer Ther., July 1, 2008; 7(7): 2051 - 2059. [Abstract] [Full Text] [PDF]