A RETROVIRAL WILD-TYPE P53 EXPRESSION VECTOR PENETRATES HUMAN LUNG-CANCER SPHEROIDS AND INHIBITS GROWTH BY INDUCING APOPTOSIS

Multicellular tumor spheroids approximate the three-dimensional config uration of primary and metastatic tumors. The effects of retrovirus-me diated transduction of wild-type p53 (wt-P53) were studied on multicel lular tumor spheroids of human non-small cell lung cancer cell lines H 322a, the p53 gene of which is homozygously mutated at codon 248, and WT226b, which has endogenous wt-p53. The growth of WT226b spheroids wa s not affected by exogenous wt-p53 transduction; the growth of H322a s pheroids, however, was significantly inhibited by the addition of wt-p 53 virus stocks. Transduction of cells by the wt-p53 retroviral vector and penetration of multiple cell layers in H322a spheroids was demons trated by in situ polymerase chain reaction/hybridization with the neo mycin-resistant neo probe. Apoptotic changes indicating programmed cel l death were observed in H322a spheroids treated with the wt-p53 virus . These results suggest that retroviral vectors can penetrate into mul tiple cell layers of three-dimensional tumor masses and induce potenti ally therapeutic effects.