John W Lippert | PubMed Health

PubMed2006

Vascular disrupting agents.

A clear definition for vascular targeting agents (VTAs) and vascular disrupting agents (VDAs) has separated the two as distinct methods of cancer treatment. VDAs differ from VTAs (antiangiogenesis drugs) in their mechanism of action. VTAs attempt to keep new blood vessels from forming and do not act on blood vessels that already feed existing tumors. In contrast, VDAs cause the vascular structure inside a solid tumor to collapse, depriving the tumor of blood and oxygen it needs to survive. Therefore, VDAs are an attractive way to approach the cancer problem by combating developed tumors. The following review discusses six small molecule VDAs, namely DMXAA, ZD6126, TZT1027, CA4P, AVE8062, and Oxi4503, their synthesis, biological mechanism of action, and current clinical status.

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PubMed2004

Comparative preclinical pharmacokinetic and metabolic studies of the combretastatin prodrugs combretastatin A4 phosphate and A1 phosphate.

PURPOSE: Combretastatin A4 phosphate (CA4P) and its structural analog, combretastatin A1 phosphate (CA1P), are soluble prodrugs capable of interacting with tubulin and causing rapid vascular shutdown within tumors. CA4P has completed Phase I clinical trials, but recent preclinical studies have shown that CA1P displays a greater antitumor effect than the combretastatin A4 (CA4) analog at equal doses. The aim of this study, therefore, is to compare pharmacokinetics and metabolism of the two compounds to determine whether pharmacokinetics plays a role in their differential activity. EXPERIMENTAL DESIGN: NMRI mice bearing MAC29 tumors received injection with either CA4P or CA1P at a therapeutic dose of 150 mg x kg(-1), and profiles of both compounds and their metabolites analyzed by a sensitive and specific liquid chromatography/mass spectroscopy method. RESULTS: The metabolic profile of both compounds is complex, with up to 14 metabolites being detected for combretastatin A1 (CA1) in the plasma. Many of these metabolites have been identified by liquid chromatography/mass spectroscopy. Initial studies, however, focused on the active components CA4 and CA1, where plasma and tumor areas under the curve were 18.4 and 60.1 microg x h x ml(-1) for CA4, and 10.4 and 13.1 microg x h x ml(-1) for CA1, respectively. In vitro metabolic comparisons of the two compounds strongly suggest that CA1 is metabolized to a more reactive species than the CA4. CONCLUSIONS: Although in vitro studies suggest that variable rates of tumor-specific prodrug dephosphorylation may explain these differences in pharmacokinetics profiles, the improved antitumor activity and altered pharmacokinetic profile of CA1 may be due to the formation of a more reactive metabolite.

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