Inhibition In Vivo

Since the target of AP is the endothelial cell, it is expected that an indiscriminate variety of tumor types can be inhibited by AP in vivo (Table 1).

Studies reported by O'Reilly et al. (8) show that systemic administration of AP leads to regression of malignant tumors and maintenance of the tumors in a dormant state. These studies also show that their findings are associated with a prolonged blockade of angiogenesis (8). AP is not cytotoxic, but cytostatic, for cultured endothelial cells in vitro. The question arises: What causes the regression and dormancy of micrometastases and solid tumors? The elegant work by Holmgren et al. (18) may provide an explanation for the effects on micrometastases. In that study, it was shown that dormancy of micrometastases is explained by a state of high tumor-cell proliferation balanced by an equally high cell death rate. Holmgren et al. s uggested that angiogenesis inhibitors, such as AP, control metastatic growth by indirectly increasing apoptosis in tumor cells.

O'Reilly et al. (8) showed that, in fact, the proliferative index for tumors treated with AP was the same as that of untreated tumors. It was the apoptotic index that was more than fourfold higher for tumors treated with AP, compared to that of untreated tumors. The studies reported by O'Reilly et al. (8,9) show that AP can induce a state of harmless dormancy that has not been possible with conventional treatments so far. These works pave the way to begin addressing the feasibility of dormancy therapy of tumors.

The therapeutic regression of primary tumors without toxicity has not been previously documented. In the studies with human AP, aggressive murine primary tumor growth was inhibited by 81-87% at doses of 50 mg/kg given subcutaneously every 12 h, seen for the duration of the experiment of 60 d in some studies (8). There was no weight loss, bleeding, hair loss, growth abnormalities, or other toxicity in the treated animals, including those receiving 100 mg/kg/d, the maximum dose tested, of either human AP derived from elastase cleavage of plasminogen or recombinant human AP (8,15). It should be noted, however, that formal toxicity studies on AP have yet to be reported.

Most standard chemotherapy regimens are associated with significant toxicity and development of resistance with continued use. There have been no formal immunogenic-ity studies reported to date on AP. Treatment of immunocompromised mice transplanted with a human breast carcinoma, with human AP delivered at 50 mg/kg twice daily, maintained the tumor in a dormant state, with no evidence of resistance for the duration of the experiment of 60 d (8).

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