Saturday, March 28, 2009

Use of Bioconjugates in Apoptosis

The study of apotosis, the programmed death of cells, has direct applications to cancer a disease where tumor cells have developed mechanisms to avoid it and multiply without control. The fact that apoptosis is usually mediated by some cell receptors makes conjugates a valuable tool in elucidating apoptosis’ mechanisms as well drug development as the following examples show:

* For instance a conjugate of anti-CD33 antibody and the amphipathic peptide KLA target efficiently CD33-positive myeloid leukemia cell lines to cause their apoptotic death induced by the D-(KLAKLAK)2 proapoptotic peptide.
* Cells over-expressing erbB2 and resistant to apoptosis can be killed more efficiently by a conjugate composed of an erbB2-binding heptapeptide conjugated to the proapoptotic a-tocopheryl succinate (a-TOS) rather than the unconjugated a-TOS. Use of the conjugate resulted in breast carcinomas in a breast cancer prone transgenic mouse strain.
* Recently it has been shown that conjugates of cytochrome c and oligoarginine linked by a thioether resulted in an increased entry into the cell, compared to cyt. c alone, and increase in apoptotic activity. In contrast a conjugate linked by a disulfide bond although entered into the cell did not enhance the apoptotic activity.
* In some cases the carrier moiety can be a synthetic polymer such as poly-L-glutamic acid to which the drug paclitaxel has been conjugated. The actual mechanism of action is still being elucidated. Another carrier that has been used successfully are the cyclodextrins to which small pro-apoptotic agents can be linked.

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