Regulation of cancer progression by inhibition of angiogenesis and induction of apoptosis.

Abstract

Potent thymidine phosphorylase (TP) inhibitors with anti-angiogenic activity are required to improve the prognosis of patients with TP-positive tumors. We have designed and developed novel structural and functional classes of TP inhibitors that also inhibit TP-induced angiogenesis, i.e. (i) the first purine analogue inhibitor of TP (7DX), (ii) the first multifunctional TP inhibitor (TP65), and (iii) the purine riboside analogue KIN59, which inhibits TP without interacting with the substrate-binding sites. The latter finding indicates that a, yet unidentified, allosteric site in TP contributes to its biological activities. In order to identify the amino acid residues in TP that interact with KIN59, we performed co-crystallograpy of the KIN59-TP complex. Our preliminary data suggest the existence of a putative KIN59 binding site. Identification of the allosteric site(s) in TP is important to gain more insight into the different biological activities of TP and may aid in the design of novel TP inhibitors. The nucleotide analogue cidofovir, which is being used clinically for the treatment of cytomegalovirus-induced retinitis in AIDS patients, emerged as a promising antitumor agent. So far, cidofovir has only been evaluated clinically for the treatment of HPV-associated tumors. Our results demonstrate the potent activity of cidofovir against tumors that are not associated with a virus. Cidofovir inhibits the growth of strongly vascularized tumors via inhibition of the growth factor FGF2, and by increasing the expression of the tumor suppressor p53, leading to apoptosis. These exciting results open new perspectives for the use of cidofovir as an anti-tumor agent in the therapy of tumors that are not associated with an oncogenic virus.