Recombinant adenovirus-mediated transfer of the wild-type p53 gene into monolayer cultures or multicellular tumor spheroids of human non-small cell lung cancer cell line H358, which has a homozygous deletion of p53, markedly increased the cellular sensitivity of these cells to the chemotherapeutic drug cisplatin. Treated cells underwent apoptosis with specific DNA fragmentation. Direct injection of the p53-adenovirus construct into H358 tumors s.c. implanted into nu/nu mice, followed by i.p. administration of cisplatin, induced massive apoptotic destruction of the tumors. These results support the clinical application of a regimen combining gene replacement using replication-deficient wild-type p53 adenovirus and DNA-damaging drugs for treatment of human cancer.

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This work was partially supported by Grant RO1 CA45187 from the National Cancer Institute (to. J. A. R.), Training Grants CA09611 (to J. A. R.) and CA45225 (to E. A. G.), gifts to the Division of Surgery from Tenneco and Exxon for the Core Lab Facility, the University of Texas M. D. Anderson Cancer Center Core Grant CA16672 and a generous gift from the Mathers Foundation.

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