Chemosensitive NCI-H69 cells and a multidrug-resistant variant, H69AR cells, were compared for chemosensitivity in vitro and in vivo. In vitro, IC50 values for cisplatin (CIS), doxorubicin (DOX), etoposide (ETO), vinorelbine (VRL), taxol (TAX), and gemcitabine (GEM) were determined under flavin-protecting conditions (Granzow et al., Cancer Res. 95, 4837, 1995). In NCI-H69 cells and H69AR cells, the respective IC50 values were 225 and 126 nM for CIS; 25 and 553 nM for DOX; 721 and 21,308 nM for ETO; 1.58 and 10.7 nM for VRL; 2.84 and 5.18 nM for TAX; and 6.8 and 5.1 nM for GEM. These results suggest collateral sensitivity of H69AR cells to CIS and GEM (Heuser et al., Cancer Lett., in press). In vivo, both cell strains were transplanted first s.c. to five nude mice each. The resulting tumors were implanted by surgical orthotopic implantation into the lungs of additional mice. For each drug and cell strain tested, 7 mice were used with standard protocols. Control animals received saline. Necropsy, tumor weight determination, and pathohistological examination were performed either at the time of death or one year after tumor implantation. Heterotopic s.c. tumors developed in 5/5 and 4/5 mice transplanted s.c. with NCI-H69 cells or H69AR cells, respectively. Orthotopic lung tumors developed in 4/7 and 1/7 of the control mice implanted with NCI-H69 and with H69AR hybrid tumors, respectively. In NCI-H69 tumor-bearing mice treated with CIS, DOX, VRL, TAX, and GEM, lung tumors developed in 0/7, 1/7, 1/7, 2/7, and 5/7 animals, respectively. Mice treated with TAX or GEM survived as long as the controls; those mice treated with CIS, DOX, and VRL survived longer. The ETO group could not be evaluated. In mice bearing H69AR tumors, lung tumors developed in 3/7, 3/7, 2/7, 4/7, 3/7, and 4/7 of the animals treated with CIS, DOX, ETO, VRL, TAX, and GEM, respectively. Compared to the control group, average survival was shorter in all treated groups. In conclusion, in vivo results on chemosensitive NCI-H69 cell-derived orthotopic tumors correlated with the in vitro results. Paradoxically in orthotopic tumors derived from drug-resistant H69AR cells chemotherapy, regardless of the actual drug response of the tumor cells in vitro, consistently led to strikingly increased tumor takes and death acceleration. This outcome resembles frequent clinical observations in lung cancer patients after chemotherapy. Further studies will determine if altered pulmonary immune responses to H69AR cells are involved in the paradoxical chemotherapy effects. Acknowledgements: The authors thank Dr. Susan P.C. Cole for the gift of H69AR cells. Supported in part by LVA Baden-Wuerttemberg, Germany.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]