To evaluate the concept that transfer of the human
carboxylesterase (CE) gene will overcome the drug resistance of a solid
tumor to
CPT-11 (
irinotecan), we used an adenovirus vector (AdCMV.CE) carrying human CE
cDNA to infect CPT-11-resistant A549 human
adenocarcinoma cells (A549/
CPT) in vitro and in vivo and evaluated cell growth over time. The A549/
CPT cells, selected by stepwise and continuous exposure of parental A549 cells to
CPT-11 over 10 months, had a 6-fold resistance to
CPT-11 and 42% CE activity in comparison with parental A549 cells. AdCMV.CE
infection resulted in an increase in functional CE
protein in resistant cells in vitro that was sufficient to convert
CPT-11 to its active metabolite,
SN-38, and effectively suppressed resistant cell growth in vitro in the presence of
CPT-11. When AdCMV.CE was directly injected into established s.c. resistant A549-based
tumors in nude mice receiving
CPT-11, there was a 1.8-fold reduction in
tumor size at day 20 compared to that of controls (P < 0.05). These observations suggest that adenovirus-mediated gene transfer of the human CE gene and concomitant administration of
CPT-11 may have potential as a strategy for local control of acquired
CPT-11 resistance of solid
tumors.