Ovarian cancer is the leading cause of gynecologic cancer death in the United States, and there is substantial need for the development of improved strategies to treat this disease. The long-term objectives of this proposal are to develop and test approaches for increasing the safety and efficacy of the chemotherapy of peritoneal tumors, such as those found in patients with advanced ovarian cancer. Based on pharmacokinetic theory, we have proposed """"""""inverse targeting"""""""" strategies that utilize adjuvant agents (e.g., anti-drug antibodies, lipid emulsions) to impart regio-selective alterations in drug disposition, thereby enhancing the therapeutic selectivity of intraperitoneal (i.p.) chemotherapy. Additionally, based on pharmacokinetic theory regarding the limiting effects of tumor blood flow on the depth of drug penetration within peritoneal tumors, we have proposed that anti-angiogenic agents may be used to produce tumor-specific increases in drug exposure following i.p. chemotherapy. Work proposed in Aim #1 will investigate the determinants of anti-drug antibody effects on the systemic exposure of antineoplastics following i.p. administration, and clinically relevant murine xenograft models of human ovarian cancer will be employed to test the hypotheses that anti-drug antibodies will increase the pharmacokinetic selectivity and therapeutic selectivity of i.p. chemotherapy.
Aim #2 will examine the effects of lipid emulsions on the disposition, toxicity, and anti-tumor effects of vinorelbine (a model lipophilic anti-cancer drug). This work will test hypotheses related to the use of exogenous lipid to modulate drug - lipoprotein interactions, as a means of inducing regio-specific alterations in pharmacokinetics and pharmacodynamics.
Aim #3 will employ anti-VEGF antibodies to test the hypothesis that anti-angiogenic therapy will increase drug exposure in peritoneal tumors following i.p. chemotherapy. The proposed work, which builds on exciting preliminary data, will allow further development of improved strategies for the treatment of ovarian cancer. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA118213-01A1
Application #
7144306
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Fu, Yali
Project Start
2006-09-13
Project End
2010-07-31
Budget Start
2006-09-13
Budget End
2007-07-31
Support Year
1
Fiscal Year
2006
Total Cost
$277,164
Indirect Cost
Name
State University of New York at Buffalo
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
038633251
City
Buffalo
State
NY
Country
United States
Zip Code
14260
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Shah, Dhaval K; Balthasar, Joseph P (2014) Predicting the effects of 8C2, a monoclonal anti-topotecan antibody, on plasma and tissue disposition of topotecan. J Pharmacokinet Pharmacodyn 41:55-69
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Duan, Xiaotao; Abuqayyas, Lubna; Dai, Lipeng et al. (2012) High-throughput method development for sensitive, accurate, and reproducible quantification of therapeutic monoclonal antibodies in tissues using orthogonal array optimization and nano liquid chromatography/selected reaction monitoring mass spectrometry. Anal Chem 84:4373-82
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Shah, Dhaval K; Balthasar, Joseph P (2011) Physiologically based pharmacokinetic model for topotecan in mice. J Pharmacokinet Pharmacodyn 38:121-42
Urva, Shweta R; Balthasar, Joseph P (2010) Target mediated disposition of T84.66, a monoclonal anti-CEA antibody: application in the detection of colorectal cancer xenografts. MAbs 2:67-72
Shah, Dhaval K; Shin, Beom Soo; Veith, Jean et al. (2009) Use of an anti-vascular endothelial growth factor antibody in a pharmacokinetic strategy to increase the efficacy of intraperitoneal chemotherapy. J Pharmacol Exp Ther 329:580-91
Wang, W; Wang, E Q; Balthasar, J P (2008) Monoclonal antibody pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther 84:548-58

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