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Patterns of In Vitro Drug Resistance in Adenocarcinoma and Squamous Cell Carcinoma of the Lung
I. Yu1, E. Mechetner1, R. Parker1, J. P. Fruehauf2, M. Gu1. 1Oncotech, Inc., Tustin, CA, 2University of California at Irvine, Irvine, CA,
BACKGROUND:
Despite the number of recent clinical trials showing a survival advantage offered by platinum-based adjuvant chemotherapy, results of standard empirical treatments are poor due to the prevalence of drug resistance in advanced non-small cell lung cancer (NSCLC). Overall patterns and specific mechanisms defining treatment response remain mostly unclear, and even less is known about patterns of drug resistance in different histologic subtypes of NSCLC. This study examined the profiles of in vitro chemoresistance to agents used in combination chemotherapy in two of the most predominant NSCLC histologic subtypes: adenocarcinoma (ADCA) and squamous cell carcinoma (SQCA). In vitro drug response testing of candidate chemotherapy agents may serve to characterize individual patient drug response and facilitate rational selection of alternative agents in NSCLC.
METHODS:
Cell suspensions were prepared from freshly resected NSCLC surgical biopsies and analyzed for in vitro drug resistance in semi-solid agarose cultures using 5-day suprapharmacologic exposures to single agents (carboplatin, cisplatin, paclitaxel, docetaxel, etoposide, topotecan, gemcitabine, and vinorelbine), using the Extreme Drug Resistance (EDR) assay. Based on tritiated thymidine uptake, the percentage cell growth inhibition (PCI) for individual drugs was compared with PCI from untreated control cultures. Histological evaluation of tissue derived from each tumor specimen was performed by two independent pathologists. Student’s t-test (2-tailed) was applied for statistical analysis.
RESULTS:
A total of 520 NSCLC specimens, 356 ADCA and 164 SQCA, were evaluated from April 2003 through July 2006. Table 1 shows in vitro drug response profiles for these histologic subtypes exposed to various single agents. The levels of drug resistance were significantly higher in ADCA for carboplatin (PCI value of 62 ± 21 vs 74 ± 14 in SQCA, p<0.0001), cisplatin (68 ± 20 vs 79 ± 16 in SQCA, p<0.0001), paclitaxel (40 ± 20 vs 46 ± 20 in SQCA, p=0.0028), and docetaxel (52 ± 23 vs 58 ± 18 in ADCA, p=0.0220), with a similar statistical trend for vinorelbine (78 ± 20 vs 81 ± 20 in SQCA, p=0.0800). A reverse trend was observed for gemcitabine: 37 ± 32 in ADCA vs 30 ± 30 in SQCA (p=0.0502). There were no differences in in vitro drug response between the two histologic subtypes for etoposide and topotecan.
CONCLUSIONS:
ADCA and SQCA showed distinct chemoresponse profiles, with higher levels of in vitro resistance to platinum and taxane compounds in ADCA. These data suggest that in vitro drug resistance testing should be considered as a tool for optimizing chemotherapy regimens in various histologic subtypes and warrant prospective clinical trials designed to assess the use of chemoresponse assays in predicting clinical outcomes for resected NSCLC.
Table 1. In vitro drug response to single agents in ADCA versus SQCA of the lung| Drugs Tested | Adenocarcinoma | Squamous Cell Carcinoma | Student’s t-test | | PCI (Mean ± SD) | Number of Cases | PCI (Mean ± SD) | Number of Cases | P-value (2-sided) | | Carboplatin | 62 ± 21 | 291 | 74 ± 14 | 131 | <0.0001 | | Cisplatin | 68 ± 20 | 265 | 79 ± 16 | 124 | <0.0001 | | Paclitaxel | 40 ± 20 | 305 | 46 ± 20 | 140 | 0.0028 | | Docetaxel | 52 ± 23 | 214 | 58 ± 18 | 95 | 0.0220 | | Etoposide | 70 ± 19 | 276 | 68 ± 21 | 116 | 0.2461 | | Topotecan | 67 ± 20 | 271 | 67 ± 20 | 121 | 0.8915 | | Gemcitabine | 37 ± 32 | 274 | 30± 30 | 110 | 0.0502 | | Vinorelbine | 78 ± 20 | 289 | 81 ± 20 | 134 | 0.0800 |
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