Endostatin, a 20kDa C-terminal fragment of collagen XVIII, is a potent inhibitor of primary tumor growth and endothelial cell proliferation and migration.
Collagen XVIII is a recently reported member of a family of collagen-like proteins, referred to as the multiplexins, and is localized mainly in a perivascular position around blood vessels.
Recombinant endostatin potently inhibited angiogenesis, maintains metastases at low level and suppressed tumors, a reduction of over 150-fold. Endostatin showed no toxicity to mice, no evidence of drug resistance, and no regrowth of tumors. [2]
Endostatin and TNP-470 treatments inhibited atherosclerosis by 85% and 70%, respectively. Either treatment significantly inhibited plaque growth, but the degree of inhibition by endostatin was less than that by TNP-470. Significant inhibition of plaque growth by endostatin or TNP-470 was seen even when the treatment was delayed until 32 weeks, although the degree of inhibition was smaller. Both endostatin and TNP-470 are reversible inhibitors of endothelial cell proliferation and appear to exert few effects on quiescent nonproliferating endothelium. [1]
Endostatin administered continuously into the peritoneal cavity by a mini-osmotic pump is 50% more effective in tumor suppression than the same dose administered once a day i.p. Furthermore, we show that a 10-fold lower dose, when given continuously, will accomplish the same tumor suppression as a single dose given i.p daily. Finally, we show that only continuous dosing can achieve tumor regression with human soluble endostatin. Endostatin retains biological activity in the osmotic pump for at least 7 days. Importantly, the endostatin does not undergo any obvious proteolytic degradation within an i.p. implanted pump. Soluble recombinant mouse endostatin (derived from P. pastoris) has shown efficacy against a human renal carcinoma in mice when given i.p as a single bolus dose of 10 –20 mg/kg/day. However, only 30% of animals in the treated group demonstrated tumor regression. [3]
References:
[1]. Moulton KS, Heller E, Konerding MA et al. Angiogenesis inhibitors endostatin or TNP-470 reduce intimal neovascularization and plaque growth in apolipoprotein E-deficient mice. Circulation. 1999 Apr 6;99(13):1726-32.
[2]. O'Reilly MS, Boehm T, Shing Y et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell. 1997 Jan 24;88(2):277-85.
[3]. Kisker O, Becker CM, Prox D et al. Continuous administration of endostatin by intraperitoneally implanted osmotic pump improves the efficacy and potency of therapy in a mouse xenograft tumor model. Cancer Res. 2001 Oct 15;61(20):7669-74.