Purpose: Potent chemotherapy regimes for non small cell lung cancer (NSCLC) are limited by their significant systemic toxicity. Combination therapy using pharmacologic agents with synergistic cytotoxic effects may reduce dosages and thus toxicity without a diminished biological response. Retinoic acids play important regulatory roles in cellular differentiation and proliferation in normal and malignant cells. The purpose of our study was to investigate the potential synergistic cytotoxic effects of the combination of RA and chemotherapeutic agents in NSCLC cells in vitro. Methods: Eight NSCLC cell lines are exposed to 9-cis RA (9cRA at 1 or 5 μM) for 48 hrs prior to treating with RA and cisplatin (CDDP) for 96 hrs (RA/RA+CDDP). Cell proliferations were quantitated by MTT assays. Controls are cells similarly treated with CDDP in the absence of RA. Two other treatment schedules are also studied: concurrent 9cRA and CDDP for 96 hrs (RA+CDDP) or sequential 9cRA (72 hrs) followed by CDDP for 96 hrs (RA/CDDP). Results: Mild growth inhibition is noted in 3 cell lines treated with 5 μM of 9cRA for 6 days. Five cell lines (Calu-6, H460, H292, H358, H1299) demonstrate enhanced sensitivity to CDDP as indicated by significantly lower IC50 values (30%, 38%, 35%, 51% and 62% of controls respectively, p<0.05 by paired t-test, n=5). The magnitude of RA-induced chemosensitization is dependent on the 9cRA doses and the treatment schedules [cisplatin IC50, μg/ml, mean (SEM), *p<0.05 vs control] (see attached table). Similar observations are made when cells are treated with VP-16 or Adriamycin. There is no sensitization of primary fibroblasts to CDDP toxicity by 9cRA. Conclusions: Combination therapy of RA and chemotherapeutic agents in NSCLC results in significant synergistic cytotoxicity against NSCLC cells. The best treatment schedules appear to be those with concurrent 9cRA and drug exposure. Clinical Implications: Combination of conventional chemotherapy with 9cRA may result in enhanced antitumor effect. Biologic synergism would allow dosage reduction and thus minimize toxicity. Cell lines Calu-6 H460 H292 H358 H1299 Control 1.57 (0.10) 1.39 (0.06) 2.07 (0.20) 5.25 (0.53) 2.00 (0.16) ra/ra+cddp 1.00 (0.05)* 0.79 (0.04)* 1.82 (0.12) 5.60 (1.17) 2.80 (0.35) (1μM) ra/ra+cddp 0.47 (0.19)* 0.52 (0.12)* 0.71 (0.22)* 2.65 (0.58)* 1.24 (0.10)* (5μM) ra+cddp 0.78 (0.27)* 0.63 (0.19)* 1.00 (0.22)* 2.80 (0.69)* 0.76 (0.10)* (5 μM) ra/cddp 0.94 (0.06)* 0.99 (0.22)* 2.75 (0.15) 6.58 (0.79) -. (5 μM).
|Original language||English (US)|
|Issue number||4 SUPPL.|
|State||Published - Oct 1 1998|
ASJC Scopus subject areas
- Pulmonary and Respiratory Medicine
- Critical Care and Intensive Care Medicine
- Cardiology and Cardiovascular Medicine