PT  - JOURNAL ARTICLE
AU  - Susan E. Bates
AU  - Wilma Y. Medina-Pérez
AU  - Glenda Kohlhagen
AU  - Smitha Antony
AU  - Tim Nadjem
AU  - Robert W. Robey
AU  - Yves Pommier
TI  - ABCG2 Mediates Differential Resistance to SN-38 (7-Ethyl-10-hydroxycamptothecin) and Homocamptothecins
AID  - 10.1124/jpet.103.063149
DP  - 2004 Aug 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 836--842
VI  - 310
IP  - 2
4099  - http://jpet.aspetjournals.org/content/310/2/836.short
4100  - http://jpet.aspetjournals.org/content/310/2/836.full
SO  - J Pharmacol Exp Ther2004 Aug 01; 310
AB  - One activity potentially limiting the efficacy of camptothecin anticancer agents is their cellular efflux by the ATP-binding cassette half-transporter, ABCG2. Homocamptothecins are novel anticancer drugs that inhibit topoisomerase 1 with a greater potency than camptothecins. Homocamptothecins differ from camptothecins by their E-ring, which is seven-membered instead of the six-membered ring of camptothecins. We report herein that, like camptothecins, homocamptothecin and its difluoro derivative BN80915 are substrates for ABCG2. However, the resistance of three selected cell lines overexpressing wild-type or mutant ABCG2 to homocamptothecin or BN80915 was less than resistance to SN-38 (7-ethyl-10-hydroxycamptothecin), indicating that both the seven-membered E-ring present in homocamptothecin and the A- and B-ring modifications present in SN-38 are involved in substrate recognition by ABCG2. HEK-293 cells transfected with vectors encoding wild-type or mutant ABCG2 were found to be less resistant to both homocamptothecins than to SN-38. However, transfectants overexpressing mutant ABCG2 had relative resistance values for homocamptothecin and BN80915 4- to 14-fold higher than cells expressing wild-type ABCG2, suggesting that the gain of function resulting from mutation at amino acid 482, although not affecting SN-38, extends to the homocamptothecins. Resistance was reversed by the ABCG2 inhibitor fumitremorgin C. BN80915 was 17-fold more potent than SN-38 in wild-type ABCG2-transfected cells, suggesting that BN80915 has the potential to overcome ABCG2-related resistance to SN-38, the active metabolite of CPT-11 (irinotecan).