Damage of the kinesin heavy chain gene contributes to the antagonism of cisplatin and paclitaxel.
Paclitaxel (TAX) and cisplatin (DDP) rank among the most promising anti-neoplastic agents for the treatment of epithelial cancer. Pre-clinical and clinical data show that the cytotoxicity resulting from the combined use of TAX and DDP is governed by the order (TAX prior DDP) > (DDP prior TAX). Since this also occurs with DNA damaging agents other than DDP, damage of a sensitivity gene may be of importance. Recently, a role of kinesin heavy chain (KHC) was uncovered for the cytotoxicity of many natural drug derivatives by use of genetic suppressor elements (Gudkov et al. (1994) Proc. Natl. Acad. Sci. USA, 91, 3744-3748). We first confirmed the dependency on the order of addition for TAX and DDP in human leukemic K562 cells taking apoptotic fraction and cell growth as endpoints. We then inhibited KHC gene expression by antisense oligodeoxy-nucleotides or KHC protein function by monoclonal antibody SUK4. Both approaches led to a reduced cytotoxicity of TAX indicating that KHC may confer sensitivity to TAX. Using a PCR-stop assay, we found that DDP indeed caused dose related DNA damage in the KHC gene. There was more DNA damage in the KHC gene than in four other genes (AFP, G6PD, MDR1, TCR-delta). Increasing doses of DDP down-regulated KHC mRNA expression more than of G6PD. There may therefore be a role of KHC for the use of TAX and DDP in combination.
Efferth
T
T
Department for Internal Medicine IV, University Hospital, RWTH Aachen, Germany. tseffert@viro.med.uni-erlangen.de
Fabry
U
U
Osieka
R
R
D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002945:Cisplatin / Q000378:metabolism* / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects; D004336:Drug Antagonism; D006801:Humans; D020014:K562 Cells; D016547:Kinesins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D016376:Oligonucleotides, Antisense; D017239:Paclitaxel / Q000378:metabolism* / Q000494:pharmacology
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D016376:Oligonucleotides, Antisense; D016547:Kinesins; D017239:Paclitaxel; D002945:Cisplatin