美国《科学》杂志电子版Science Magazine 1996 Vol.274 No.5286 - 0373.docxVIP

美国《科学》杂志电子版Science Magazine 1996 Vol.274 No.5286 - 0373.docx

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SCIENCE ? VOL. 274 ? 18 OCTOBER 1996 SCIENCE ? VOL. 274 ? 18 OCTOBER 1996 PAGE \* MERGEFORMAT # SCIENCE ? VOL. 274 ? 18 OCTOBER 1996 SCIENCE ? VOL. 274 ? 18 OCTOBER 1996 PAGE \* MERGEFORMAT # ■ RESEARCH ARTICLE An Adenovirus Mutant That Replicates Selectively in p53- Deficient Human Tumor Cells An Adenovirus Mutant That Replicates Selectively in p53- Deficient Human Tumor Cells James R. Bischoff,* David H. Kirn, Angelica Williams, Carla Heise, Sharon Horn, Mike Muna,Lelia Ng,* Julie A. Nye, Adam Sampson-Johannes, Ali Fattaey,Frank McCormickt The human adenovirus E1B gene encodes a 55-kilodalton protein that inactivates the cellular tumorsuppressor protein p53. Here it is shown that a mutant adenovirus that does not express this viral protein can replicate in and lyse p53-deficient human tumor cells but not cells with functional p53. Ectopic expression of the 55-kilodalton EIB protein in the latter cells rendered them sensitive to infection with the mutant virus. Injection of the mutant virus into p53-deficient human cervical carcinomas grown in nude mice caused a significant reduction in tumor size and caused complete regression of 60 percent of the tumors. These data raise the possibility that mutant adenoviruses can be used to treat certain human tumors. Deletion or mutation of the p53 tumor suppressor gene occurs frequently in most types of human cancer (I )? Tumors lacking functional p53 are, in many cases, refractory to chemotherapy or radiation (2). It is therefore critically important to develop therapeutic strategies to treat p5 3-deficient tumors. DNA tumor viruses such as adenoviruses infect quiescent cells and induce them into the S phase of the cell cycle so that viral DNA replication can proceed (3). The El A protein of human adenoviruses, which binds pRB, p300, and other related proteins, is largely responsible for this forced entry into the S phase (4). The EIB region of the viral genome encodes a 55-kD protein (EIB 55K) that binds and inactivat

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