Topoisomerase I-DNA Complex Stability Induced by Camptothecins and Its Role in Drug Activity&#

Randy   M.   Wadkins; David      Bearss; Govindarajan      Manikumar; Mansukhlal   C.   Wani; Monroe   E.   Wall; Daniel   D. Von   Hoff

Abstract

The mechanism of cytotoxicity of the camptothecin family of antitumor drugs is thought to be the consequence of a collision between moving replication forks and camptothecin-stabilized cleavable DNA-topoisomerase I complexes. One property of camptothecin analogs relevant to their potent antitumor activity is the slow reversal of the cleavable complexes formed with these drugs. The persistence of cleavable complexes with time may be an essential property for increasing the likelihood of a collision between the replication fork and a cleavable complex, giving rise to lethal DNA lesions. In this paper, we examined a number of camptothecin analogs forming cleavable complexes with distinctly different stabilities. Absolute reaction rate analysis was carried out for each derivative. Our results indicate that the stability of the cleavable complex is dominated by the activation entropy (ΔS†) of the reversal process. We measured the relative lipophilicity of the CPT analogs by reverse-phase HPLC, but the ΔS† of complex reversal is not directly related to the lipophilicity of the CPT analog being used. We suggest that solvent ordering around the 7- through 10-position of the CPT ring may be responsible for reversal rates dependence on ΔS†. We demonstrate that the cleavable complex stability conferred by each camptothecin analog is directly correlated with the induction of apoptosis and cytotoxicity to tumor cells.

Keywords: topoisomerase I, camptothecin, cleavable complex, stability, water solubility, kinetics, entropic control

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