Hypothesis: Optimal use of photodynamic sensitizing agents, such as motexafin lutetium (LuTex) or Pc4, or radiation sensitizing agents, such as motexafin gadolinium (GdTex), involves delivering energy at an optimal time related to tissue concentrations of the agent and the difference in concentrations present in normal and malignant tissues. We believe that the concentrations of these agents can be detected non-invasively with an innovative technique and that such data will be useful in clinical trial design and therapeutic decisions. We propose to use the optical characteristics of LuTex, Pc4 and GdTex to compare their pharmacokinetics, as determined using the non-invasive optical pharmacokinetics system (OPS), with concentrations defined by standard, destructive HPLC analysis.
Our specific aims are: -To optimize the use of OPS for measurement of tissue concentrations of LuTex, GdTex and Pc4 in various matrices. Develop the most appropriate matrix for in vitro calibrations of LuTex, GdTex and Pc4 by OPS. -To determine, with HPLC, the pharmacokinetics and tissue distribution of LuTex, Pc4 and GdTex in mice bearing human tumor xenografts. LuTex and Pc4 will be evaluated in SCID mice bearing human cervical carcinoma xenografts (C-33A) and human breast adenocarcinoma xenografts (MDA-MB-23 1), while GdTex will be evaluated in mice bearing human head and neck squamous cell carcinoma xenografts (1483). -To determine distribution of these agents using non-invasive OPS in the same mice, tumors, adjacent tissue, and skin. -To evaluate the optimum concentration and time after administration of LuTex, GdTex or Pc4 for initiation of laser or radiation treatment, and follow the pharmacodynamic effects by monitoring tumor growth and the induction of apoptosis by both cytochrome c measurements and TUNEL assay. -To extend the pre-clinical findings in Specific Aims 1 through 4 into clinical protocols in CID, breast, and head and neck cancer. We believe these initial studies will provide data necessary to design clinical trials using this methodology to non-invasively assess concentrations of these clinically relevant agents in accessible tumors. In that the photodynamic therapy and radiation oncology programs at UPCI have ongoing clinical protocols involving LuTex and GdTex, initiation of clinical trials evaluating OPS should be expeditious, of obvious importance and likely to lead to a broader programmatic approach to the issues addressed in this project.
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