[DNA repair as a determinant of tumour chemosensitivity].
Differently from target-based anticancer drugs, molecular mechanisms of actions are not well-known in many of the classical antineoplastic agents. With the exception of vinca alkaloids and taxanes, all of the classical antineoplastic agents work on DNA metabolism in cells and can therefore be categorised as 'DNA metabolism inhibitor'. Cellular sensitivity against these drugs largely depends on various activities in DNA metabolism, particularly in DNA repair. However, DNA repair as a determinant of drug sensitivity had long received little attention. DNA mismatch repair (MMR) is now regarded as an important determinant to alter cellular sensitivities against various drugs including fluoropyrimidines, platinum compounds and topoisomerase inhibitors. However, molecular mechanisms of this connection are still unknown. In particular, the relationship between MMR and 5-fluorouraci (l 5-FU) sensitivity is now being approached by examining the tumour MMR status and clinical outcomes in colorectal cancer patients treated with 5-FU-based adjuvant chemotherapies. However, reported results lack consistency, possibly due to the methodological problems in assays used to determine the MMR status. On the other hand, nucleotide excision repair (NER) is also regarded as an important determinant of cisplatin (CDDP) sensitivity. Expression of ERCC 1, a component of this complex multi-protein system, has been reported to be a determinant of prognosis in CDDP-treated non-small-cell lung cancer patients. In order to establish the significance of DNA repair as a determinant of tumour chemosensitivity, further basic studies, particularly ones approached from biochemical viewpoints, are required. Clinical studies supported by accurate assay techniques are also needed.
Oda
Shinya
S
Cancer Genetics Laboratory, Kyushu University.
Kuraoka
Isao
I
Maehara
Yoshihiko
Y
D011125:Adenomatous Polyposis Coli / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002945:Cisplatin / Q000494:pharmacology; D004247:DNA / Q000378:metabolism*; D053843:DNA Mismatch Repair; D004260:DNA Repair / Q000502:physiology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004247:DNA; D002945:Cisplatin; D005472:Fluorouracil