2003 Fiscal Year Final Research Report Summary
The prediction of adverse effect and determination of the maximum tolerated dose in chemotherapy of lung cancer based on clinical and molecular pharmacology
| Project/Area Number |
14570551
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Respiratory organ internal medicine
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| Research Institution | HIROSHIMA UNIVERSITY |
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Principal Investigator |
KONDO Keiichi Hiroshima University, Medical and Dental Hospital, Research Associate, 医学部・歯学部附属病院, 助手 (20332827)
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| Co-Investigator(Kenkyū-buntansha) |
TANIGAWARA Yusuke Keio University, Faculty of Medicine, Professor, 医学部, 教授 (30179832)
HAMADA Akinobu Kumamoto University, Medical and Dental Hospital, Assistant Professor, 医学部附属病院, 講師 (00322313)
NAKAJIMA Masamitsu Hiroshima University, Medical and Dental Hospital, Assistant Professor, 医学部・歯学部附属病院, 講師 (20198097)
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| Project Period (FY) |
2002 – 2003
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| Keywords | TDM / PK / PD / Paclitaxel / Carboplatin / Irinotecan Hydrochloride / Docetaxel / CYP / UGT |
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| Research Abstract |
Recently, the combination of paclitaxel (TAX) and carboplatin (CBDCA) has been reported one of the standard chemotherapies in patients with advanced non-small cell lung cancer. Although dose limiting toxicity of CBDCA is thrombocytopenia, it is known that the toxicity is decreased by the combination of TAX. Therefore, we conducted a phase I study of the combination with CBDCA and TAX in patients with non small cell lung cancer to determine the maximum-tolerated dose of them, and investigate the relationship between thrombocytopenia and serum thrombopoietin (TPO) kinetics by the clinical and molecular pharmacological studies. CBDCA was administered at a target area under the curve (AUC) of 6 mg×min/ml and in combination with escalating doses of TAX per cohort in 4 steps from 180 to 225 mg/m^2. Blood samples for CBDCA kinetics and TPO kinetics were collected. Thirteen patients were enrolled and grade 3 or 4 treatment-related leucocytopenia and neutropenia occurred, however, dose-limiting
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toxicity was not observed. The negative correlation between TPO day 8/day 1 and the nadir of thrombocytes which occurred at administration of CBDCA as a single agent, was not observed in the combination. The actual measured AUC of CBDCA and the rate of decreased thrombocytes diminished significantly in the combination compared with CBDCA alone. This study demonstrated that the recommended doses were 210 mg/m^2 of TAX, with CBDCA targeting AUC of 6 mg×min/ml. Moreover, the inhibitory effect of thrombocytopenia was observed in the combination. Accompanied with this phase I study, blood samples were collected and mRNA were isolated from peripheral mononuclear cells. The gene expressions of CYP3A4 and CYP2C8 in peripheral mononuclear cells were quantified with real-time PCR system at Kumamoto University. As a result, there was no change in levels of gene expressions before and after the administration of TAX. This result clarified that the administration of TAX unlike docetaxel did not induce its metabolic enzyme Less
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