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Biotech / Medical : Indications -- Cancer -- Ignore unavailable to you. Want to Upgrade?

To: seminole who wrote (6)	4/4/2001 11:29:14 PM
From: scaram(o)uche	Respond to of 1840

Raf Kinase Inhibitory Protein (RKIP) Sensitizes DU145 Human Prostate Cancer Cells to 9-Nitrocamptothecin-Triggered Apoptosis. Devasis Chatterjee, Kam Yeung, Panayotis Pantazis, John Sedivy, James Wyche, Brown University, Providence, RI. The anticancer agent 9-nitrocamptothecin (9NC) triggers apoptosis in DU145 human prostate cancer cells. In contrast, treatment of DU145 cells resistant (RC1) to 9NC with this compound results in the activation of nuclear factor kappa B (NF-kB) and leads to cell survival. In this study we examined the role of RKIP, a cytoplasmic protein that is a negative regulator of Raf-1 signaling and can inhibit the NF-kB-mediated survival response in many cell lines, in the resistance of RC1 cells to 9NC. Our results indicate that in DU145 cells, 9NC treatment leads to a time-dependent induction of RKIP. Further, transient transfection of an antisense RKIP expression vector into DU145 cells inhibits 9NC-triggered apoptosis. In RC1 cells, transient transfection of RKIP blocks 9NC-triggered NF-kB activation and sensitizes these cells to undergo apoptosis after exposure to 9NC. Collectively our results assign an integral function to RKIP in the sensitization of 9NC-responsive and -resistant DU145 human prostate cancer cells to apoptosis induction.

To: seminole who wrote (6)	4/4/2001 11:31:50 PM
From: scaram(o)uche	Read Replies (1) \| Respond to of 1840

Pre-Clinical Antitumor Activity of 9-Nitrocamptothecin (9NC) in Proprietary IDD-P™ and IDD-D™ Formulation Howard Sands, Awadhesh K. Mishra, Beth A. Hollister, Terri A. Alford, Robin Ball, Shih-Fong Chen, SuperGen, Wilmington, DE; RTP Pharma Inc.,, Nuns Island, PQ, Canada; Piedmont Research Center, Morriville, NC. 9-Nitrocamptothecin (9NC), a water-insoluble camptothecin, is in Phase III trials in patients with pancreatic cancer. Only an oral formulation of the drug is currently available for clinical use. Intravenous administration might decrease GI tract toxicity and modify drug disposition. It would also permit regional perfusion for high-dose chemotherapy restricted to a tumor site. We have evaluated two I.V. formulations, IDD-P™-9NC and IDD-D™-9NC, to determine whether 9NC has parenteral activity in nude mice bearing human tumors. The IDD-P™ and IDD-D™ formulations of 9NC were prepared by RTP Pharma Inc. using their proprietary IDD™ technology. Athymic nude mice bearing human A375 melanoma were treated intravenously with 3 and 1.5 mg/kg of 9NC as the IDD-P™ formulation and 2 and 1 mg/kg of 9NC as the IDD-D™ formulation on two cycles of a five-days-on and two-days-off schedule. The antitumor activity was compared to the activity of 9NC given orally and to the activity of two clinically available camptothecin analogs, CamptosarÒ and HycamtinÒ , at their optimal preclinical doses and schedules. The IDD-P™-9NC formulation demonstrated outstanding antitumor activity: partial or complete tumor shrinkage in some animals and 97-99% tumor growth inhibition in the remaining animals. The IDD-D™-9NC formulation was less active, inhibiting the growth of A375 tumor to a lesser degree (87%) at the maximal tolerated dose (2 mg/kg). The activity of IDD-P™-9NC was equivalent to that of the oral formulation of 9NC and superior to the activity of CamptosarÒ and HycamtinÒ . In summary, 9-nitrocamptothecin formulated in IDD-P™ has outstanding parenteral antitumor activity against human melanoma xenografts. We are investigating whether the I.V. activity of IDD-P™-9NC extends to other human tumor xenografts and how its spectrum of activity compares to that of the oral preparation.