Mike.... as you know, p53 is mutant in many cancers, and exogenous "wild type" p53 often suppresses the growth of tumor cells. Most of the work with p53 involves replication defective adenovirus vectors to deliver a wild type p53 gene. The major players there are Schering Plough (Canji) and Rhone Poulenc (Introgen), so it's sort of hard to get tons of bang for your buck. Maybe someone else knows of a route to play this........ GZMO and the Schering Plough collaboration?
Schering Plough sure is a well run R&D outfit, BTW.
However, the ONXX approach is quite different..... they use a cytopathic, replicating virus that they claim preferentially infects tumor cells that are p53 deficient.
My mind is sort of fuzzy about the discussion with Larry. I'll go back and look. But, for now, I'm in a hurry, and there's this......
Hum Gene Ther 1999 Mar 1;10(4):579-90
Targeting the replication of adenoviral gene therapy vectors to lung
cancer cells: the importance of the adenoviral E1b-55kD gene.
Hay JG, Shapiro N, Sauthoff H, Heitner S, Phupakdi W, Rom WN
Department of Medicine, New York University Medical Center, NY 10016, USA. hayj01@mcrcr6.med.nyu.edu
[Medline record in process]
It has been proposed that an adenovirus with the E1b-55kD gene deleted has a selective advantage in replicating in cancer cells
that have mutations in the p53 gene (Bischoff et al., 1996). We have explored this hypothesis in several lung cancer cell lines,
and evaluated potential mechanisms that might regulate the replication of Ad338, an E1b-55kD-deleted virus, with the
objective of developing a rational approach for targeting gene therapy to lung tumors. Our data show that Ad338 replicates
poorly in three lung cancer cell lines with various p53 mutations (H441, H446, and Calu1), yet this virus replicates to a high
level in a lung cancer cell line with wild-type p53 (A549) and in a normal lung fibroblast line (IMR90). Viral DNA replication,
expression of viral proteins, and shutoff of host cell proteins were not important variables in limiting the replication of the
E1b-55kD-deleted virus. However, the cell lines resistant to host cell protein shutoff were also the most resistant to the
cytopathic effect induced by mutant and wild-type virus and the only cells to survive for 8 days following infection. The
E1b-55kD protein clearly has an important role in viral replication beyond its interaction with p53. Thus, an E1b-55kD-deleted
virus cannot be used to specifically target viral replication to p53-mutated lung cancer cells.
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and there's this.........
J Virol 1998 Dec;72(12):9470-8
Replication of ONYX-015, a potential anticancer adenovirus, is
independent of p53 status in tumor cells.
Rothmann T, Hengstermann A, Whitaker NJ, Scheffner M, zur Hausen H
Angewandte Tumorvirologie, Deutsches Krebsforschungszentrum, 69120 Heidelberg, Germany.
The 55-kDa E1B protein of adenovirus, which binds to and inactivates the tumor suppressor protein p53, is not expressed in
the adenoviral mutant termed ONYX-015 (i.e., dl1520). It was reported that the mutant virus due to a deletion in E1B is able
to replicate only in cells deficient for wild-type p53. Accordingly, dl1520 is currently being evaluated as a potential tool in the
therapy of p53 deficient cancers. In contrast, we report here that dl1520 replicates independently of the p53 status in various
tumor cell lines (U87, RKO, A549, H1299, and U373). In addition, the inhibition of p53-mediated transcriptional activation in
wild-type p53 containing U2OS cells, by overexpression of a transdominant negative p53 mutant, did not render the cells
permissive for dl1520 replication. Finally, we show that, depending on the multiplicity of infection, the deleted virus is able to
replicate in and to kill primary human cells. Thus, the molecular basis for the growth differences of dl1520 within different cell
types remains to be determined.
************
So..... I presume that I was looking at the encouraging clinical results and asking...... "huh? Why does it seem to be working?" zur Hausen is not exactly a lightweight. |
