Cisplatin is an active agent in the treatment of both small cell (SCLC) and non small cell lung cancer (NSCLC). We have generated two pairs of cisplatin resistant SCLC (SCLC/SR-2.1 SCLCB/BC1) and two pairs of NSCLC lung cancer cell lines (NSCLCS/SC, NSCLCAL/ALC). All parental cell lines were derived from patients’ tumors. Both SR2.1 and BC1 exhibit 25 fold resistance to cisplatin and 20 fold resistance to carboplatin but did not show resistance to oxaliplatin. NSCLCSC and NSCLCALC exhibit 6 fold resistance to cisplatin and 4 fold resistance to carboplatin. SCLCBV was developed by intermittent exposure to VP-16 and exhibits 8 fold resistance to VP-16 due to alteration in topoisomerase II protein expression. SCLCR overexpresses P-gp and possesses MDR1 phenotype. SCLCA overexpresses MRP1 and possesses MRP1 phenotype. Next, we have examined the gene expression profile in these resistant sublines using the microarray(purchased from Super-Array) that included signal transduction pathway genes. We have found that all resistant cell lines have increased cyclin D1 mRNA expression. Since flavopiridol (FP) is known to down regulate cyclin D1 transcription and arrest cells at G1/S boundaries and G2M, we have studied the antitumor activity of FP in these resistant cell lines. The concentration that inhibits cell growth by 50% (IC50) was calculated. The results are as follows: SCLC1(66nM), SR2.1(47.5nM), SCLCB (50.2nM), SCLCBC1(61.6nM), SCLCBV(61nM), SCLCR(100.4nM), SCLCA(61.6nM), NSCLCAL(107.2nM), NSCLCALC(52.4nM), NSCLCS(95.8nM), and NSCLCSC (79.8nM). Thus, our data indicate that FP is active in all but one SCLC resistant subline(SCLCR). SCLCR exhibits 1.5 resistance to FP when compared with their parental cells. FP also is active in NSCLC and their cisplatin resistant variants. Combination of a non toxic dose of FP (22nM) with taxotere either before, simultaneously or after did not increase the growth inhibitory effect of taxotere, However, treatment with 22 nM of FP potentiated the growth inhibitory effect of cisplatin as shown below. Thus our data indicate that FP is active in cisplatin resistant as well as topoisomerase II and MRP1 resistant lung cancer cell lines. FP also potentiates the antitumor activity of cisplatin but not taxotere. Combination of FP and cisplatin may be useful in the future treatment of lung cancer. This work was supported by VA research fund and by Aventis Pharmaceuticals.

[Proc Amer Assoc Cancer Res, Volume 45, 2004]