Abstract
Purpose. To evaluate chemosensitivity and its correlation with expression levels of the multidrug resistant transporter (MDR1) and the multidrug resistance-associated proteins 1 and 2 (MRP1, MRP2) mRNA in human colorectal adenocarcinomas.
Methods. Colorectal adenocarcinomas were obtained as surgical samples from 25 patients. The chemosensitivity of 12 anticancer drugs was assessed by the collagen gel droplet embedded culture drug sensitivity test (CD-DST). The expression levels of MDR1, MRP1, and MRP2 mRNA in colorectal adenocarcinomas were also evaluated by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR).
Results. The chemosensitivity was successfully evaluated for 16 of 25 patients, and the anticancer drugs were effective against the samples showing a relatively high growth rate. Gemcitabine hydrochloride was found to be more promising than those often prescribed for the treatment of colorectal adenocarcinoma. There was no correlation of the mRNA expression levels of MDR1 and MRP1 with the chemosensitivity of any anticancer drugs tested, but mitomycin C was found to be more effective for the colorectal adenocarcinoma with relatively high expression of MRP2 mRNA.
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A. E. Bogden, W. Griffin, S. D. Reich, M. E. Costanza, and W. R. Cobb. Predictive testing with the subrenal capsule assay. Cancer Treatment Rev. 11(supplementA):113-124 (1984).
S. E. Salmon, A. W. Hamburger, B. Soehnlen, B. G. M. Durie D. S. Alberts, and T. E. Moon. Quantitation of differential sensitivity of human-tumor stem cells to anticancer drugs. N. Engl. J. Med. 298:1321-1327 (1978).
D. D. von Hoff, J. Cowan, G. Harris, and G. Reisdorf. Human tumor cloning: feasibility and clinical correlations. Cancer Chemother. Pharmacol. 6:265-271 (1981).
M. Rozencweig, V. Hofmann, C. Sanders, W. Rombaut, U. Fruh, and G. Martz. In vitro growth of human malignancies in a cloning assay. Recent Results Cancer Res. 94:1-7 (1984).
N. Tanigawa, D. H. Kern, Y. Hikasa, and D. L. Morton. Rapid assay for evaluating the chemosensitivity of human tumors in soft agar culture. Cancer Res. 42:2159-2164 (1982).
D. H. Kern, C. R. Drogemuller, M. C. Kennedy, S. U. Hildebrand-Zanki, N. Tanigawa, and V. K. Sondak. Development of a miniaturized, improved nucleic acid precursor incorporation assay for chemosensitivity testing of human solid tumors. Cancer Res. 45:5436-5441 (1985).
T. Kondo, T. Imamura, and H. Ishihashi. In vitro test for sensitivity of tumor to carcinostatic agents. Jpn. J. Cancer Res. (Gann) 57:113-121 (1966).
T. Mosmann. Rapid colorometric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Methods 65:55-63 (1983).
J. Carmichael, W. G. DeGraff, A. F. Gazdar, J. D. Minna, and J. B. Mitchell. Evaluation of a tetrazolium-based semiautomated colorimetric assay: assessment of chemosensitivity testing. Cancer Res. 47:936-942 (1987).
R. A. Vescio, C. H. Redfern, T. J. Nelson, S. Ugoretz, P. H. Stern, and R. M. Hoffman. In vivo-like drug responses of human tumors growing in three-dimensional gel-supported primary culture. Proc. Natl. Acad. Sci. U.S.A. 84:5029-5033 (1987).
T. Kubota, N. Sasano, O. Abe, I. Nakao, E. Kawamura, T. Saito, M. Endo, K. Kimura, H. Demura, H. Sasano, H. Nagura, N. Ogawa, R. M. Hoffman, and the Chemosensitivity Study Group for the Histoculture Drug-Response Assay. Potential of the histoculture drug-response assay to contribute to cancer patient survival. Clin. Cancer Res. 1:1537-1543 (1995).
A. E. Freeman and R. M. Hoffman. In vivo-like growth of human tumors in vitro. Proc. Natl. Acad. Sci. U.S.A. 83:2694-2698 (1986).
H. Kobayashi, K. Tanisaka, O. Doi, K. Kodama, M. Higashiyama, H. Nakagawa, M. Miyake, T. Taki, S. Hara, M. Yasutomi, Y. Hanatani, K. Kotake, and T. Kubota. An in vitro chemosensitivity test for solid human tumors using collagen gel droplet embedded cultures. Int. J. Oncol. 11:449-455 (1997).
H. Kobayashi, M. Higashiyama, K. Minamigawa, K. Tanisaka, K. Takano, H. Yokouchi, K. Kodama, and T. Hata. Examination of in vitro chemosensitivity test using collagen gel droplet culture method with colorimetric endpoint quantification. Jpn. J. Cancer Res. 92:203-210 (2001).
Y. Takamura, H. Kobayashi, T. Taguchi, K. Motoyama, H. Inaji, S. Noguchi. Prediction of chemotherapeutic response by collagen gel droplet embedded culture-drug sensitivity test in human breast cancers. Int. J. Cancer 98:450-455 (2002).
N. Tanigawa, A. Kitaoka, M. Yamakawa, K. Tanisaka, and H. Kobayashi. In vitro chemosensitivity testing of human tumors by collagen gel droplet culture and image analysis. Anticancer Res. 16:1925-1930 (1996).
M. Higashiyama, K. Kodama, H. Yokouchi, K. Takami, O. Doi, H. Kobayashi, K. Tanisaka, and K. Minamigawa. Immunohistochemical p53 protein status in nonsmall cell lung cancer is a promising indicator in determining in vitro chemosensitivity to some anticancer drugs. J. Surg. Oncol. 68:19-24 (1998).
M. Higashiyama, Y. Miyoshi, K. Kodama, H. Yokouchi, K. Takami, M. Nishijima, T. Nakayama, H. Kobayashi, K. Minamigawa, and Y. Nakamura. p53-regulated GML gene expression in non-small cell lung cancer: a promising relationship to cisplatin chemosensitivity. Eur. J. Cancer 36:489-495 (2000).
M. Higashiyama, K. Kodama, H. Yokouchi, K. Takami, H. Nakagawa, F. Imamura, K. Minamigawa, and H. Kobayashi. Cisplatin-based chemotherapy for postoperative reccurence in non-small cell lung cancer patients: relation of the in vitro chemosensitive test to clinical response. Oncol. Rep. 8:279-283 (2001).
Y. Hanatani, H. Kobayashi, S. Kodaira, H. Takami, T. Asagoe, E. Kaneshiro An in vitro chemosensitivity test for gastric cancer using collagen gel droplet embedded culture. Oncol. Rep. 7:1027-1033 (2000).
H. Yasuda, T. Takada, K. Wada, H. Amano, T. Isaka, M. Yoshida, T. Uchida, and N. Toyota. A new in-vitro drug sensitivity test (collagen-gel droplet embedded-culture drug sensitivity test) in carcinomas of pancreas and biliary tract: possible clinical utility. J. Hepatobiliary Pancreat. Surg. 5:261-268 (1998).
T. Sakaeda, T. Nakamura, and K. Okumura. MDR1 genotype-related pharmacokinetics and pharmacodynamics. Biol. Pharm. Bull. 25:1391-1400 (2002).
T. Sakaeda, T. Nakamura, and K. Okumura. Pharmacogenetics of MDR1 and its impact on the pharmacokinetics and pharmacodynamics of drugs. Pharmacogenomics 4:397-410 (2003).
R. G. Tirona and R. B. Kim. Pharmacogenomics of drug transporters. In J. Licinio and M.-L. Wong (eds.), Pharmacogenomics. The Search for Individualized Therapies, Wiley-VCH Verlag GmbH, Germany, 2002, pp. 179-213.
T. Nakamura, T. Sakaeda, N. Ohmoto, T. Tamura, N. Aoyama, T. Shirakawa, T. Kamigaki, T. Nakamura, K. I. Kim, S. R. Kim, Y. Kuroda, M. Matsuo, M. Kasuga, and K. Okumura. Real-time quantitative polymerase chain reaction for MDR1, MRP1, MRP2, and CYP3A-mRNA levels in Caco-2 cell lines, human duodenal enterocytes, normal colorectal tissues, and colorectal adenocarcinomas. Drug Metab. Dispos. 30:4-6 (2002).
T. Nakamura, T. Sakaeda, M. Horinouchi, T. Tamura, N. Aoyama, T. Shirakawa, M. Matsuo, M. Kasuga, and K. Okumura. Effect of the mutation (C3435T) at exon 26 of the MDR1 gene on expression level of MDR1 messenger ribonucleic acid in duodenal enterocytes of healthy Japanese subjects. Clin. Pharmacol. Ther. 71:297-303 (2002).
T. Sakaeda, T. Nakamura, M. Hirai, T. Kimura, A. Wada, T. Yagami H. Kobayashi, S. Nagata, N. Okamura, T. Yoshikawa, T. Shirakawa, A. Gotoh, M. Matsuo, and K. Okumura. MDR1 upregulated by apoptotic stimuli suppresses apoptotic signaling. Pharm. Res. 19:1323-1329 (2002).
Y.-W. Liu, T. Sakaeda, K. Takara, T. Nakamura, N. Ohmoto, C. Komoto, H. Kobayashi, T. Yagami, N. Okamura, and K. Okumura. Effects of reactive oxygen species on cell proliferation and death in HeLa and its MDR1-overexpressing derivative cell line. Biol. Pharm. Bull. 26:278-281 (2003).
M. Kool, M. de Haas, G. L. Scheffer, R. J. Scheper, M. J. van Eijk, J. A. Jujin, and P. Borst. Analysis of expression of cMOAT (MRP2), MRP3, MRP4, and MRP5, homologues of the multi-drug resistance-associated protein gene (MRP1), in human cancer cell lines. Cancer Res. 57:3537-3547 (1997).
X. Y. Chu, Y. Kato, and Y. Sugiyama. Multiplicity of biliary excretion mechanisms for irinotecan, CPT-11, and its metabolites in rats. Cancer Res. 57:1934-1938 (1997).
E. Hinoshita, T. Uchiumi, K. Taguchi, N. Kinukawa, M. Tsuneyoshi, Y. Maehara, K. Sugimachi, and M. Kuwano. Increased expression of an ATP-binding cassette superfamily transporter, multidrug resistance protein 2, in human colorectal carcinoma. Clin. Cancer Res. 6:2401-2407 (2000).
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Nakahara, T., Sakaeda, T., Nakamura, T. et al. Chemosensitivity Assessed by Collagen Gel Droplet Embedded Culture Drug Sensitivity Test, and MDR1, MRP1, and MRP2 mRNA Expression in Human Colorectal Adenocarcinomas. Pharm Res 21, 406–412 (2004). https://doi.org/10.1023/B:PHAM.0000019292.03875.3e
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DOI: https://doi.org/10.1023/B:PHAM.0000019292.03875.3e