Main

Pharmacological doses of endostatin, a C-terminal fragment of collagen XVIII with relative molecular mass 20,000, at very low concentrations may be deposited in the extracellular matrix with each cycle of therapy, analogous to amyloid deposits in patients with light-chain disease. The marked shrinkage of the mouse tumours from approximately 250-450 mm3 to 5-50 mm3 could effectively increase the local extracellular matrix concentration of endostatin 5-50 fold. Each successive cycle of regrowth followed by treatment and regression could progressively increase the concentration of endostatin in the local extracellular matrix until the concentration is sufficient to inhibit further angiogenesis.

This phenomenon of preferential concentration could explain the observation of a dormant primary tumour while the same tumour type inoculated at a distant site would be uninhibited. The extracellular matrix concentration of endostatin at these distant sites could be several log factors below the concentration at the primary tumour site and insufficient to inhibit tumour-driven angiogenesis.

If this hypothesis is correct, it could mean Boehm et al. have serendipitously discovered the ideal way to administer endostatin therapy, delivering a high inhibitory concentration of endostatin at the primary tumour site while keeping the systemic extracellular matrix concentration below the level necessary to inhibit naturally occurring angiogenesis such as wound healing. An assay of the relative concentration of endostatin at the primary tumour site compared to distant tissue concentration should establish if this is the basis for the observed phenomenon.