Factors affecting sensitivity to antitumor platinum derivatives of human colorectal tumor cell lines.
OBJECTIVE
The aim of this study is to examine the factors affecting sensitivity to cisplatin, carboplatin, and oxaliplatin in human colorectal tumor cell lines.


METHODS
Caco-2, DLD-1, HCT-15, HCT116, LS180, SW620, and WiDr cells were used. Their growth inhibition by platinum derivatives was evaluated with a WST-1 assay utilizing succinate dehydrogenase activity. Cellular accumulation and DNA-binding of platinum were measured with an inductively coupled plasma mass spectrometer. The mRNA levels of copper transporters (hCtr1, ATP7A, and ATP7B) and organic cation transporters (hOCT1, hOCT2, and hOCT3) were evaluated by the real-time reverse transcription-PCR method using SYBR green.


RESULTS
The cytotoxicity of platinum derivatives ranked oxaliplatin > cisplatin > carboplatin in almost all cells used. Cellular accumulation and DNA-binding of platinum varied among the types of cells, but levels were similar on treatment with cisplatin and oxaliplatin, and lower in response to carboplatin. The levels of copper and organic cation transporter mRNAs also differed with cell type. A correlation analysis revealed that sensitivity to platinum derivatives was dependent in part on the amount of platinum bound to DNA. In addition, the cellular accumulation of platinum and level of ATP7A mRNA may be factors affecting the cytotoxicity of cisplatin, while the cytotoxicity of oxaliplatin was suggested to be affected by the levels of ATP7A and hOCT1 mRNAs.


CONCLUSIONS
Some factors affecting the sensitivity of tumor cells to platinum derivatives were proposed, and will provide useful information for cancer chemotherapy with platinum derivatives.
Kitada
Noriaki
N
Department of Hospital Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto, 607-8414, Japan.
Takara
Kohji
K
Minegaki
Tetsuya
T
Itoh
Chihiro
C
Tsujimoto
Masayuki
M
Sakaeda
Toshiyuki
T
Yokoyama
Teruyoshi
T
D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018938:Caco-2 Cells; D016190:Carboplatin / Q000378:metabolism / Q000494:pharmacology*; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000378:metabolism / Q000494:pharmacology*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D000073840:Copper-Transporting ATPases; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D050811:Octamer Transcription Factor-1 / Q000235:genetics / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000075102:Organic Cation Transporter 2; D009944:Organoplatinum Compounds / Q000378:metabolism / Q000494:pharmacology*; D000077150:Oxaliplatin; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000378:metabolism; D000099254:Organic Cation Transporter 3
D000251:Adenosine Triphosphatases; D000970:Antineoplastic Agents; D016190:Carboplatin; D027682:Cation Transport Proteins; D002945:Cisplatin; D000073840:Copper-Transporting ATPases; D050811:Octamer Transcription Factor-1; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D012697:Serine Endopeptidases; D013385:Succinate Dehydrogenase; D000099254:Organic Cation Transporter 3; C494165:POU2F1 protein, human; C491013:SLC22A2 protein, human; C105139:CTRL protein, human; C081184:ATP7A protein, human; C000612464:ATP7B protein, human