Abstract 3525: Molecular determinants of the anticancer efficacy of indenoisoquinolines
Authors: Siu Annie Fung-Ming , Leung Duncan Chung-Hang 
Published: February 2011

Topoisomerase I (top1) is a validated target for the anticancer alkaloid camptothecin and its analogs (CPTs). CPTs are the only class of topoisomerase I (top1) inhibitors approved for cancer treatment in clinic. However, CPTs have pharmacologic and clinical limitations. This leads to the development of noncamptothecins, such as indenoisoquinolines (INDs), as novel top1 inhibitors. Currently three INDs have been selected as leads for clinical development by the National Cancer Institute [1]. INDs are endowed with favorable characteristics. Persistence of top1 cleavage complexes induced by INDs is higher than that of induced by CPTs. The top1 cleavage sites trapped by the INDs have different genomic locations, implying differential targeting of cancer cell genomes. Presently, we demonstrate that molecular dynamics and bioinformatics are valuable tools for the study of molecular determinants of anticancer drugs.

Our previous molecular dynamics studies revealed that the most persistent CPTs have higher calculated free-energy barriers for drug dissociation from the flanking base pairs [2]. We have recently extended our studies to INDs. We found the INDs have higher calculated free-energy barriers when compared with that of CPTs. This may explain why INDs experimentally produce more persistent top1 cleavage complexes when compared with that of CPTs [3]. The National Cancer Institute (NCI)-60 panel consists of 60 human tumor cell lines established for screening anticancer efficacy of a larger number of molecules, including INDs. To deciphering the relationships between anticancer efficacy of INDs and the characteristics of the cancer cells, the molecular profile data on the NCI-60 were downloaded from the CellMiner database [4]. Integromic and bioinformatics analyses were carried out on the markers that correlated with the responses of INDs-treatments. Same and unique markers, when compared to that of CPTs, were identified for INDs. Further studies are required for the validation of these predictive markers.

References:

[1] Y. Pommier and M. Cushman, The indenoisoquinoline noncamptothecin topoisomerase I inhibitors: update and perspectives, Mol. Cancer Ther. 2009, 8, 1008.

[2] FM. Siu and CM. Che, Persistence of camptothecin analog-topoisomerase I-DNA ternary complexes: a molecular dynamics study, J. Am. Chem. Soc., 2008, 130, 17928.

[3] S. Antony, KK. Agama, ZH. Miao, K. Takagi, MH. Wright, Al. Robles, L. Varticovski, M. Nagarajan, A. Morrell, M. Cushman, Y Pommier, Novel indenoisoquinolines NSC 725776 and NSC 724998 produce persistent topoisomerase I cleavage complexes and overcome multidrug resistance, Cancer Res. 2007, 67, 10397.

[4] UT. Shankavaram, S. Varma, D. Kane, M. Sunshine, KK. Chary, WC. Reinhold, Y. Pommier, JN. Weinstein, CellMiner: a relational database and query tool for the NCI-60 cancer cell lines, BMC Genomics, 2009, 10, 277.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3525.