In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 1707-1707
Abstract:
Purpose: Pemetrexed (PEM), a multitargeted antifolate with manageable toxicity, is a most active drug against non-squamous non-small cell lung cancer (NSCLC); however, a majority of patients acquired the resistance to PEM eventually. To elucidate the mechanisms of acquired resistance to PEM, we established eight PEM-resistant NSCLC cell lines. Method: PC-9 and A549 cells (adenocarcinoma of the lung) were treated with step-wise increasing concentrations of PEM. Sublines, which were able to grow in the presence of low and high concentrations of PEM, were cloned with limiting dilutions and designated PC-9/PEML and PC-9/PEMH, respectively; A549/PEML and A549/PEMH, respectively. Growth inhibition was defined by MTT assay. Thymidylate synthase (TS), dihydrofolate reductase (DHFR), glycinamide ribonucleotide formyltransferase (GARFT) and multidrug resistance-associated protein 4 (MRP4) gene expressions and protein expressions were analyzed by quantitative reverse transcriptase PCR and immunoblotting. Result:Characteristics of PEM-resistant sublines are shown in the Table. All resistant sublines showed cross-resistant to cisplatin but not to docetaxel, vinorelbine, 5-fluorouracil and the active metabolite of irinotecan (SN-38). TS mRNA expression was significantly increased in all resistant sublines compared to the parent cells. TS mRNA expression was paralleled to the increment of TS protein. DHFR was significantly increased in the PEM-resistant A549 sublines. GARFT was not correlated with resistance to PEM. MRP4 was increased in PC-9/PEMH and A549/PEMH sublines. Conclusions: PEM-resistant NSCLC may be still sensitive to docetaxel, vinorelbine, 5-fluorouracil and irinotecan. High TS expression seems to be the primary resistant mechanism to PEM. MRP4 and DHFR expression might be elevated at higher resistance to PEM. Relative resistance (R.R.) was defined as the ratio of 50% inhibitory concentration (IC50) of resistant cells to IC50 of parent cells; *p & lt;0.05; **p & lt;0.01. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1707. doi:10.1158/1538-7445.AM2011-1707
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2011-1707
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2011
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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