lular activation signals - p53 is also involved. The human cell has evolved with a protective sys-tem which will lead to cell suicide if DNA damage cannot be adequately repaired, or if inappropri-ate cell activation signals are initiated by infectious or other events. Of course, damaged cellular DNA as well as im-proper cell activation independently have the potential to lead to very harmful consequences. This protective cell suicide system is known as programmed cell death - or - apop- tosis (the second letter p is silent). The p53 system becomes very active under such conditions.

DNA can be repaired by a number of different enzymes - and - before the cell is "allowed" to replicate the DNA (as would be required for cell division) - the damaged DNA must be repaired prior to any DNA replication/cell division. The p53 protein normally maintains the cell in G0 or in G1 arrest. If DNA repair systems "try" to repair damage to the cell's chromosome(s) - and if the repair doesn't occur well, there are interacting cell materials which signal p53 protein, and in con- cert these systems will drive the cell to commit self-destruction - cellular suicide - in a very precisely controlled manner. This type of cell death is quite different than cell death which may be caused by a virus, other intra-cellular infectious agent, or trauma. When apoptosis occurs, the chromosomes are broken into discrete fragments, and the inside contents of the cell are never released to the surrounding tissue. This lack of release of cytoplasmic contents serves to prevent inflammatory responses - which are induced when a virus or some other agent causes a cell to break apart. Thus, programmed cell death is a powerful protective response against cancer cells, against cells impro- perly activated to divide for whatever reason - and against any "rogue" cell(s) with lots of damaged and/or mutated DNA in them.

What Happens If There is Something Wrong With p53?
If there is something wrong with p53 within a single cell - either the p53 doesn't function properly, or is completely missing (damage/mutation of the gene responsible for p53 appearance), there is the potential for trouble from that cell if the cell is triggered to begin cell division. If the cell is activated to cell division by normal circumstances; or, if there is significant DNA damage (uv-light, chemicals or viral interference with cellular DNA) which may inadvertently activate the cell to divide, not only will the cell's DNA not be repaired, without a functional p53 system, the cell is now incapable of regulating cell division, and is also unable to commit suicide by apoptosis... a functional p53 protein is necessary. Therefore, a cell may become activatable because of DNA damage, or the cell may be activated under normal circumstances... but in each case, without a functional p53 protein, the cell will continue to divide - will never stop; and, all of the progeny cells will not be able to commit suicide - nor regulate their cell division either. It is estimated that fifty percent (50%) of all known cancers have a dysfunctional p53 protein - because of a mutation in the gene which encodes infor- mation for the synthesis of this protein.

What's So Unique About Adenovirus; and, What is the Involvement of p53?
Human Adenovirus normally infects human cells which are quiescent (non-dividing). But, the wild-type virus (the one which is normal in the environment) can also infect dividing cells (normal or cancer cells). In all instances - upon introduction of this virus into a human cell (viral infection), the genetic material belonging to the virus - which happens to be DNA - is activated. Two particular gene regions in the DNA of this DNA-virus are activated immediately: E1A and E1B. This activa-tion leads to the synthesis of two different viral proteins: e1a and e1b.

What Does the e1a Adenoirus Protein Do?
The viral protein, e1a, interacts specifically with certain proteins within the cell which results in driving the cell (forced entry) into what is called the S-phase (the DNA Synthesis phase) of the cell cycle - which ultimately leads to cell division (M-phase.... mitosis)... if a cell is already in this cycle - no problem - virus substances will _maintain_ the cell in this cycle. In order for this virus - Adeno- virus - to replicate its own DNA genetic material, the enzymes necessary for this process and other activation and synthesis substances within the cell are available only if the CELL's DNA activation and replication systems are turned on within the cell's nucleus. This viral activation of cellular pro- cesses allows the VIRUS to replicate its genetic material, and to synthesize all of the proteins the VIRUS needs to assemble new virus and thereby produce many, many progeny viruses.

What Else Does Adenovirus e1a Protein Do?
The action of e1a also happens to stimulate the cell's p53 system...(remember - viral activation to cell division is an improper thing... p53 acts in response to this improper activation). Theoretically, therefore, the cell will initiate activity which would normally result in G0, G1 arrest, or, cell suicide. If any of these protective events occurred, however, the virus would not be able to produce pro- geny - its host cell died too quickly, or, necessary cell systems were no longer active. For the virus - such events would be lethal to propagation of the virus. So - the virus has evolved, too.

Action of The Mutant Adenovirus on a Normal Cell
This virus has had its DNA purposefully altered such that the E1B gene region is mutated - activa-tion of this gene leads to an incorrect e1b virus protein structure (dysfunctional e1b). Consequently, when this Adenovirus mutant infects a cell, this virus CANNOT produce a functional e1b protein. ... remember - a functional e1b protein will normally interact with and interfere with functional p53 - which allows viral DNA replication to proceed well, and which prevents cell suicide initiated by p53. A normal cell will have a functional p53. So, when viral protein e1a drives the cell into S-phase there will be a concomitant response of p53 - which will lead to cell-division arrest or apoptosis eventually if this action of p53 proceeds unimpeded. Since the mutant virus does not have a functional e1b protein - the p53 system responds unimpeded - which allows repair, inhibition of viral replication, and/or which can lead the cell to commit suicide. All of these things mean that a mutant Adenovirus with this particular e1b mutation, theoretically should not replicate efficiently and therefore should not easily kill, normal cells.

Cancer Gene Therapy by Adenovirus-Mediated Gene Transfer

For more details look ath this publication of Qiaohua Wu1 , Terence Moyana3 and Jim Xiang2*

Search ww.nlv.ch