Silicon Investor (SI) -- The First Internet Community

STOCKTALK

We've detected that you're using an ad content blocking browser plug-in or feature. Ads provide a critical source of revenue to the continued operation of Silicon Investor. We ask that you disable ad blocking while on Silicon Investor in the best interests of our community. If you are not using an ad blocker but are still receiving this message, make sure your browser's tracking protection is set to the 'standard' level.

Biotech / Medical : Introgen Therapeutics -- Ignore unavailable to you. Want to Upgrade?

To: zeta1961 who wrote (496)	3/5/2006 9:18:04 PM
From: zeta1961	Read Replies (1) \| Respond to of 802

Wild type p53 and chemo-resistance Abstract Number: 5420 Presentation Title: Circumvention of drug resistance in human tumors harboring wild-type p53 Presentation Start/End Time: Wednesday, Apr 05, 2006, 8:00 AM -12:00 PM Location: Exhibit Hall, Washington Convention Center Poster Section: 14 Poster Board Number: 14 Author Block: Zahid H. Siddik, Guangan He, Masayuki Watanabe, Kalpana Mujoo, Abdul R. Khokhar, Jian Kuang. UT M.D. Anderson Cancer Center, Houston, TX A seminal player in apoptosis is the tumor suppressor p53, which is often mutated in cancers and this causes drug resistance. What is not readily appreciated is the clinical significance of drug resistance in tumors harboring wild-type p53. In fact, such tumors are highly prevalent, accounting for 35-100% of resistant breast, non-small cell lung, testicular and ovarian cancers. Moreover, resistance of wild-type p53 tumors can be significantly greater than mutant p53 tumors. In our panel of clinically resistant human ovarian cancer, the IC50 of cisplatin in mutant p53 tumors was 1.2-3.3 µM (mean, 2.0), whereas in wild-type p53 tumors this range was 2.8-9.9 µM (mean, 5.7). This represents 9- and 26-fold resistance, respectively, compared to sensitive wild-type p53 ovarian A2780 cells. A common factor to emerge was the inability of cisplatin-treated wild-type p53 resistant tumors to activate the p53/p21 pathway, which then attenuates p21-dependent inhibition of G1-phase cyclin-dependent kinase (Cdk) complexes. Activation of the p53/p21 pathway, inhibition of Cdk, and cell death were observed with DAP, a DACH-Pt(IV) analog with axial acetates. These effects of DAP were also seen in intrinsic cisplatin-resistant breast and prostate cancers harboring wild-type p53. More importantly, p21-deleted HCT-116 cell lines were 2- to 3-fold resistant to the two platinum drugs. The differential effects of cisplatin and DAP in resistant tumor cells may be due in part to the mechanism of post-translational modification to induce/activate p53. In this respect, cisplatin induces p53 phosphorylation at Ser-392 in sensitive MCF-7 cells, but DAP does not. Similarly, dephosphorylation at Ser-376 was maximal at 4 h after DAP treatment (20 µM), whereas equimolar cisplatin did not induce dephosphorylation at this time, but dephosphroylated p53 appeared by 8-16 h at about 50% of maximal levels seen with DAP. The temporal profile of Ser-15 phosphorylation and induction of total p53 mirrored dephosphorylation of Ser-376, and provides a correlative relationship between these three cellular events. Since Ser-376 dephosphorylation and a lack of Ser-392 phosphorylation are properties associated with ionizing radiation, which induces p53 in an ATM-dependent manner, we explored whether p53 induction by DAP involved ATM. Systematic knockdowns with siRNA indicated that p53 induction by cisplatin was ATR/Chk1-dependent, but not ATM/Chk2-dependent, whereas p53 induction by DAP was independent of either of these two pathways. These results demonstrate that cisplatin and DAP activate p53 through different pathways, and this provides a basis for reactivation of the p53/p21 pathway by DAP to circumvent cisplatin resistance. (Supported by NCI RO1 CA 77332, 82361 and 93941).