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International Journal of Cancer Research
  Year: 2006 | Volume: 2 | Issue: 4 | Page No.: 390-396
DOI: 10.3923/ijcr.2006.390.396
Molecular Modelling Analysis of the Metabolism of Topotecan
Fazlul Huq

Abstract:
Topotecan (TOP) is a water-soluble analogue of camptothecin, approved for use in second line therapy against ovarian carcinoma and small-cell lung cancer. TOP inhibits DNA replication and RNA transcription by stabilizing the cleavable complexes formed between nuclear enzyme topoisomerase I and DNA. There are two general types of topoisomerases: type I and type II. Type I cleaves and separates a single strand of DNA whereas type II cleaves both the DNA strands. Mammalian topoisomerase I is particularly important for supporting movement of replication fork during DNA replication and for relaxing supercoils formed during DNA transcription. The lactone ring undergoes pH-dependent reversible hydrolysis. The primary metabolite of TOP is N-desmethyltopotecan (NDMTOP). Both TOP, NDMTOP exist in the lactone ring form at low pH and open ring acid form at high pH. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that TOP and all its metabolites have small LUMO-HOMO energy differences so that they would be kinetically labile. The molecular surfaces of TOPO and NDMTOPO have some electron-deficient regions so they may be subject to nucleophilic attacks such as those by glutathione and nucleobases in DNA. The reaction with glutathione would induce cellular toxicity by compromising the antioxidant status of the cell whereas that with nucleobases would cause DNA damage. The lability of TOP and its metabolites means that the rates of such adverse reactions are likely to be significant.
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How to cite this article:

Fazlul Huq , 2006. Molecular Modelling Analysis of the Metabolism of Topotecan. International Journal of Cancer Research, 2: 390-396.

DOI: 10.3923/ijcr.2006.390.396

URL: https://scialert.net/abstract/?doi=ijcr.2006.390.396

 
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