Combined treatment of bladder cancer cell lines with lapatinib and varying chemotherapy regimens--evidence of schedule-dependent synergy.
OBJECTIVE
ErbB family members present an attractive target for therapeutic manipulation in bladder cancer. Lapatinib is an oral, small molecule, reversible dual inhibitor of ErbB1 (epidermal growth factor receptor) and ErbB2 (HER2) tyrosine kinases. Cisplatin-based combination chemotherapy has proven benefit in palliating symptoms and prolonging survival in patients with metastatic bladder cancer. In this study, we investigated the potential utility of lapatinib as an adjunct to chemotherapy in human bladder cancer cell lines. We also assessed whether these interactions were schedule dependent and synergistic.


METHODS
We chose two bladder cancer cell lines, one (RT112) with high expression of ErbB1 and ErbB2 and one (J82) with low expression of these receptors. These cell lines were used to determine the growth inhibitory effects of lapatinib and the clinically relevant combination of gemcitabine and cisplatin (GC) chemotherapy. Four different schedules were assessed: GC alone (no lapatinib); lapatinib before and during GC; lapatinib concomitant with GC; and lapatinib after GC.


RESULTS
Lapatinib reduced cell viability in both cell lines in a dose-dependent fashion. The values for the 50% inhibitory concentration for RT112 and J82 cells after lapatinib were similar. In both cell lines, the addition of lapatinib to GC potentiated the efficacy. The optimal sequence consisted of lapatinib before and during GC. Using this schedule, cooperation was synergistic.


CONCLUSIONS
Our data present evidence that lapatinib cooperates with clinically relevant cytotoxic agents and may have therapeutic utility in the management of chemotherapy-naive metastatic bladder cancer. Lapatinib may also enable reduced-dose chemotherapy, a potential toxicity-sparing strategy.
McHugh
Lynsey A
LA
Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester, United Kingdom. lamchugh@doctors.org.uk
Kriajevska
Marina
M
Mellon
John K
JK
Griffiths
Thomas R
TR
D000704:Analysis of Variance; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006801:Humans; D000077341:Lapatinib; D011799:Quinazolines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism; D012680:Sensitivity and Specificity; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000473:pathology; D000093542:Gemcitabine
D002945:Cisplatin; D003841:Deoxycytidine; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000093542:Gemcitabine