Abstract
It was with great interest that we read the report1 on the lack of acquired drug resistance to repeated doses of endostatin in experimental cancers in mice. Of particular interest is the unprecedented finding that each tumour type became indefinitely dormant after a varying number of treatment cycles. We believe one explanation for this phenomenon might be found in the clinical observation that, after complete regression of large bulky tumours, rebiopsy of the primary tumour site will frequently show large amounts of fibrosis or scarring.
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.
References
Boehm, T.et al. Nature 390, 404–407 (1997).
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Black, W., Agner, R. Tumour regression after endostatin therapy. Nature 391, 450 (1998). https://doi.org/10.1038/35064
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DOI: https://doi.org/10.1038/35064
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