Long-term cultivation of colorectal carcinoma cells with anti-cancer drugs induces drug resistance and telomere elongation: an in vitro study.
BACKGROUND
The role of telomerase activation in the expression and/or maintenance of drug resistance is not clearly understood. Therefore, we investigated the relationships, among the telomerase activity, telomere length and the expression of multidrug resistance genes in colorectal cancer cell lines cultivated with anti-cancer drugs.


METHODS
LoVo and DLD-1 cells were continuously grown in the presence of both CDDP and 5-FU for up to 100 days. Cell proliferation, telomerase activity, telomere length and the expression of multidrug resistance genes were serially monitored as the PDL increased.


RESULTS
The expression of multidrug resistance genes tended to increase as the PDL increased. However, an abnormal aneuploid clone was not detected as far as the cells were monitored by a DNA histogram analysis. Tumor cells showing resistance to anti-cancer drugs revealed a higher cell proliferation rate. The telomere length gradually increased with a progressive PDL. The telomerase activity reached a maximum level at 15 PDL in LoVo cells and at 27 PDL in DLD-1 cells. An increase in the mRNA expression of the telomerase components, especially in hTERT and in hTR, was observed at the same PDLs.


CONCLUSIONS
These results suggest that a high telomerase activity and an elongation of telomeres both appear to help maintain and/or increase drug resistance in colorectal cancer cells. Cancer cells with long telomeres and a high proliferative activity may thus be able to better survive exposure to anti-cancer drugs. This is presumably due to an increased chromosome stability and a strong expression of both mdr-1 and MRP genes.
Kuranaga
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N
Department of Surgery I, National Defense Medical College, Namiki 3-2, Tokorozawa, Saitama 359-8513, Japan. grd1409@gr.ndmc.ac.jp
Shinomiya
N
N
Mochizuki
H
H
D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D002352:Carrier Proteins / Q000096:biosynthesis; D002455:Cell Division / Q000187:drug effects; D002945:Cisplatin / Q000378:metabolism / Q000493:pharmacokinetics; D002999:Clone Cells / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism*; D004268:DNA-Binding Proteins; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D005472:Fluorouracil / Q000378:metabolism / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D019450:Genes, MDR / Q000235:genetics; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D016601:RNA-Binding Proteins; D019098:Telomerase / Q000096:biosynthesis / Q000378:metabolism; D016615:Telomere / Q000187:drug effects* / Q000235:genetics* / Q000502:physiology; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
D000970:Antineoplastic Agents; D002352:Carrier Proteins; D002945:Cisplatin; D004268:DNA-Binding Proteins; D005472:Fluorouracil; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D016601:RNA-Binding Proteins; D019098:Telomerase; C104342:TEP1 protein, human