Multiple factors other than p53 influence colon cancer sensitivity to paclitaxel
| Autor: | Shewan M. Aziz, Mark Bowers, Manni Yegappan, Ronald D. Brown, Satya Ramachandran, Neeraj Sharma, Robert Chapman, Bennett W. Yu |
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| Rok vydání: | 2000 |
| Předmět: |
Cancer Research
Paclitaxel Colorectal cancer Immunoblotting Drug resistance Toxicology chemistry.chemical_compound Pharmacokinetics Tumor Cells Cultured Carcinoma medicine Humans Doubling time Pharmacology (medical) Polymorphism Single-Stranded Conformational Pharmacology business.industry Cell Cycle Exons Cell cycle Genes p53 medicine.disease Antineoplastic Agents Phytogenic Multiple drug resistance Oncology chemistry Colonic Neoplasms Immunology Cancer research business Cell Division |
| Zdroj: | Cancer Chemotherapy and Pharmacology. 46:329-337 |
| ISSN: | 1432-0843 0344-5704 |
| Popis: | Purpose: To determine factors which influence the sensitivity of human colorectal carcinoma cell lines to paclitaxel. Methods: The paclitaxel sensitivity of ten human colorectal carcinoma cell lines, and a panel of RKO colon carcinoma cell lines, isogenic except for p53 status, were studied. The inhibitory concentrations causing a 50% decrease in growth (IC50) were assayed after 3, 24, and 96 h after paclitaxel exposure. The doubling time (DT) and cell cycle parameters of cells were also measured. The expression of the multidrug resistance glycoprotein-1 (MDR-1), bcl-2 and bax was quantitatively assessed by immunoblotting. Results: Mean IC50 values at 24 and 96 h drug exposure were about 1.5 logs lower than the IC50 values at 3 h, regardless of the p53 status. No difference was found between the IC50 values of wild-type and mutant p53 cells, or among the RKO panel of cells. Correlation analysis showed that: (1) resistance was associated with longer DTs, but this was generally abated by a 96-h exposure; (2) with a 3-h exposure, the combination of MDR, bcl-2 and bax parameters with DT (DT + MDR + bcl-2–bax) best correlated with IC50 values (r=0.77); (3) with a 96-h exposure, in spite of the generally decreased IC50 values, a combination of MDR-1, bcl-2 and bax parameters (MDR + bcl-2–bax) best correlated with the IC50 values (r=0.71). Conclusions: These results suggest that the exposure duration, DT, and expression of MDR-1, bcl-2 and bax each contribute to paclitaxel sensitivity of human colorectal carcinoma cells. In assessing paclitaxel drug resistance, multiple factors should always be considered. There may be a therapeutic window for taxanes in colon cancer by optimizing pharmacokinetics and modulating MDR-1 and bcl-2 resistance factors. |
| Databáze: | OpenAIRE |
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