Inhibition of Topoisomerase I by Anti-Cancer Drug Altered the Endometrial Cyclicity and Receptivity

Abstract

Topoisomerase I (topo I) is an essential nuclear enzyme involved in virtually all aspects of gene expression, and is the target of the anti-cancer drugs- camptothecin (CPT) and its derivatives. Improvement of the survival rates of young women with cancer has led to the consideration of the effects of long-term chemotherapy on their fertility. The effect of anticancer drugs on ovarian function was previously investigated; however, no reports are available concerning their effect on the endometrium, whose integrity is an important factor in embryo implantation. Here we used a rat animal model to investigate the expression and activity of topo I in the various physiologic phases of the endometrium and the influence of CPT on its integrity and receptivity. The results show, for the first time, that the endometrial topo I level and activity are influenced by the physiologic phases of the endometrium (estrous cycle) and correlate with the estrogen blood concentration. Treatment with the anti-cancer drug CPT caused histological disruption of the endometrium and deleterious effect on its cyclicity. Moreover, CPT treatment significantly reduced the implantation rate of embryos, suggesting alteration in the receptivity of the endometrium. These results suggest that topo I is important for maintaining the normal physiologic cyclicity and functionality of the endometrium in rats. Anti-cancer agents that target topo I severely impair estrous cycle progression and endometrial integrity and receptivity, emphasizing the importance of addressing the effect of chemotherapy on the endometrial functionality.

DNA Topoisomerase as Drug Target in unicellular protozoan parasite Leishmania donovani

“…14 In humans, Top1 and Top2 both enzymes bind to the regions of the pre-replicative complex in cells during the various phases, including M, early G1, and G1/S, to control the initiation of replication from the origins. [15][16][17] DNA topoisomerase II plays an essential part in chromosomal decatenation. 8…”

Natural Compounds as Anticancer Agents Targeting DNA Topoisomerases

“…DNA topoisomerases are also essential for embryonic development in mammals [ 53 ]. In humans, TOP1 and TOP2 proteins bind to the regions of the pre-replicative complex in cells during the M, early G1, and G1/S phases of the cell cycle to control the firing of replication origins [ 37 , 54 , 55 ].…”