Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance

Abstract

Acquired drug resistance is a major problem in the treatment of cancer. Of the more than 500,000 annual deaths from cancer in the United States, many follow the development of resistance to chemotherapy. The emergence of resistance depends in part on the genetic instability, heterogeneity and high mutational rate of tumour cells. In contrast, endothelial cells are genetically stable, homogeneous and have a low mutational rate. Therefore, antiangiogenic therapy directed against a tumour's endothelial cells should, in principle, induce little or no drug resistance. Endostatin, a potent angiogenesis inhibitor, was administered to mice bearing Lewis lung carcinoma, T241 fibrosarcoma or B16F10 melanoma. Treatment was stopped when tumours had regressed. Tumours were then allowed to re-grow and endostatin therapy was resumed. After 6, 4 or 2 treatment cycles, respectively, no tumours recurred after discontinuation of therapy. These experiments show that drug resistance does not develop in three tumour types treated with a potent angiogenesis inhibitor. An unexpected finding is that repeated cycles of antiangiogenic therapy are followed by prolonged tumour dormancy without further therapy.

The uPA/uPAR system regulates the bioavailability of PDGF-DD: implications for tumour growth

“…Exponentially growing cells (1  10 6 ) were implanted subcutaneously in the midline dorsum of each mouse. Tumour volume was monitored and calculated using the formula: width 2  length  0.52 (Boehm et al, 1997) and when any of the tumours reached 1000 mm 3 , all tumours were excised and fixated in 4% paraformaldehyde. Animal experiments were approved by the local committee for animal experiments and performed according to United Kingdom Coordinating Committee on Cancer Research guidelines (1998).…”

Increased endostatin/collagen XVIII expression correlates with elevated VEGF level and poor prognosis in hepatocellular carcinoma

“…9 Among these inhibitors, endostatin, a 20-kDa protein derived from carboxy (C)-terminal proteolytic fragment of collagen XVIII (C18), has attracted tremendous attention since its discovery because of its potency to inhibit neovascularization and tumor growth without inducing drug resistance in mice. 10,11 The role of endostatin/C18 expression during liver cirrhosis or HCC progression remains controversial despite previous studies. [12][13][14][15] In the present study, we analyzed endostatin/C18 expression in HCC cell lines as well as clinical specimens, thereby to delineate the involvement of endostatin/C18 expression in liver carcinogenesis.…”

Systemic gene therapy with anti-angiogenic factors inhibits spontaneous breast tumor growth and metastasis in MMTVneu transgenic mice

“…Highly promising results on experimental tumors in rodents using these inhibitors as purified proteins as well as transduced genes, alone or in combination with traditional therapies have been reported. [3][4][5][6][7] The establishment of a dormancy status, which in some cases persists even after the suspension of therapy, has been obtained with these gene products, 5 and this, together with the absence of drug resistance, 8 raised the possibility that the anti-angiogenic effects could be useful in the treatment of human tumors.…”