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Improved chemoradiotherapy of lung cancer

Institution: California Pacific Medical Center Research Institute
Investigator(s): Li-Xi Yang, M.D., Ph.D.
Award Cycle: 2005 (Cycle 14) Grant #: 14RT-0177 Award: $659,033
Subject Area: Cancer
Award Type: Research Project Awards

Initial Award Abstract
Topotecan is a new anticancer drug in 1990s for the treatment of human recurrent small cell lung cancer. However, toxic side effects such as neutropenia and thrombocytopenia have limited the usefulness of this drug. We are seeking to develop and test a novel second-generation version of topotecan that is more effective in killing human lung cancer cells as a radiation enhancement agent, but less toxic to normal tissues. Our preliminary results indicate that this second-generation analog is substantially more effective against lung cancer cells than topotecan. It also exhibited 100% curative effects on mouse mammary tumors in mice, but none with topotecan. Moreover, this analog is significantly less toxic to normal mice than topotecan. The key active structure of this analog is highly stable in human plasma, but not that of topotecan.

We plan to test this promising analog on two types of human lung cancers grown in nude mice, and to evaluate its therapeutic efficacy at clinically relevant doses for future application in human lung cancer therapy. In these studies its drug effects will be evaluated alone and in combination with radiotherapy, compared to those of topotecan. These preclinical studies of this nature are complex and laborious, but they provide essential information on therapeutic properties of topotecan analog under clinically relevant conditions. Based on preliminary results it is hoped that these novel topotecan analog will be superior to topotecan, providing a unique combination of improved therapeutic action in killing lung cancer cells without any penalty in the form of increased drug toxicity. If therapeutic effects similar to those noted in tissue culture and in mice could be achieved on human lung cancers, the clinical benefits would be substantial.

Therefore, the development of newly synthesized second-generation topotecan analog with higher efficacy and reduced toxicity holds a considerable promise for dramatically improved therapy of lung cancers. The proposed studies in this project will directly contribute to the design of clinical trials and to the development of this novel topotecan analog as a clinically useful therapeutic agent for conquering lung cancers.

A Novel Camptotheicin Analog with Enhanced Anitiumor Activity
Periodical: Anticancer Research Index Medicus:
Authors: Yount G, Yang Y, Wong B, Wang HJ, and Yang LX ART
Yr: 2007 Vol: Nbr: Abs: Pg:

A Novel Camptotheicin Analog with Enhanced Antitumor Activity
Periodical: Anticancer Research Index Medicus:
Authors: Li-Xi Yang ABS
Yr: 2007 Vol: Nbr: Abs: Pg:

Novel camptothecin derivatives.
Periodical: In Vivo Index Medicus:
Authors: Legarza, K, Yang LX ART
Yr: 2005 Vol: 19 Nbr: Abs: Pg: 283-292

New molecular mechanisms of action of camptothecin-type drugs.
Periodical: Anticancer Research Index Medicus:
Authors: Legarza k. Yang LX ART
Yr: 2006 Vol: 26 Nbr: 5 Abs: Pg: 3301-3306

Design, synthesis and development of novel camptothecin drugs.
Periodical: Current Pharmaceutical Design Index Medicus:
Authors: Lieu T, Yang LX ART
Yr: 2008 Vol: 14 Nbr: 11 Abs: Pg: 1078-1097

gamma-H2AX - A novel biomarker for DNA double-strand breaks.
Periodical: In Vivo Index Medicus:
Authors: Kuo L, Yang LX ART
Yr: 2008 Vol: 22 Nbr: 3 Abs: Pg: 305-310

Enhancement of radiation-induced DNA damage and inhibition of its repair by a novel camptothecin analog.
Periodical: Anticancer Research Index Medicus:
Authors: Huang G, Wang HJ, Yang LX ART
Yr: 2009 Vol: Nbr: Abs: Pg: