Investigation of Novel Doxorubicin Analogs for Treatment of Soft Tissue Sarcomas
Faculty Mentor Information
Don L. Warner, Ph.D. Kenneth Cornell, Ph.D.
Abstract
Doxorubicin (DOX) is one of the primary drugs used to treat soft tissue sarcoma (STS). However, it shows only a 30% overall response rate, and the comprehensive STS survival rate that has not improved in the last 50 years. DOX causes significant side effects, including cardiotoxicity and irreversible congestive heart failure. To improve drug efficacy and reduce cardiotoxicity, three DOX derivatives (P-DOX, GPX-150, GPX-160) were synthesized and their 50% inhibitory concentrations (IC50’s) were determined for a panel of STS cell lines. P-DOX showed activity against HT1080 fibrosarcoma (IC50 0.1 nM – 1.0 nM) that was a thousand-fold more potent than DOX (IC50 0.1 - 1 μM). GPX-150 and GPX-160 compounds showed activity that was similar to, or better than DOX. According to this data, P-DOX could be a better chemotherapeutic agent than DOX, with a decreased cumulative dose. Drug transport studies were conducted on Caco-2 cell monolayers to investigate drug permeability properties, and begin to explore their pharmacokinetics. Finally, the results of preliminary anti-sarcoma drug activity studies in mouse tumor xenograft models of STS will be presented.
Investigation of Novel Doxorubicin Analogs for Treatment of Soft Tissue Sarcomas
Doxorubicin (DOX) is one of the primary drugs used to treat soft tissue sarcoma (STS). However, it shows only a 30% overall response rate, and the comprehensive STS survival rate that has not improved in the last 50 years. DOX causes significant side effects, including cardiotoxicity and irreversible congestive heart failure. To improve drug efficacy and reduce cardiotoxicity, three DOX derivatives (P-DOX, GPX-150, GPX-160) were synthesized and their 50% inhibitory concentrations (IC50’s) were determined for a panel of STS cell lines. P-DOX showed activity against HT1080 fibrosarcoma (IC50 0.1 nM – 1.0 nM) that was a thousand-fold more potent than DOX (IC50 0.1 - 1 μM). GPX-150 and GPX-160 compounds showed activity that was similar to, or better than DOX. According to this data, P-DOX could be a better chemotherapeutic agent than DOX, with a decreased cumulative dose. Drug transport studies were conducted on Caco-2 cell monolayers to investigate drug permeability properties, and begin to explore their pharmacokinetics. Finally, the results of preliminary anti-sarcoma drug activity studies in mouse tumor xenograft models of STS will be presented.