Author: Roger Vassy ; Samia Mourah ; Marie-Astrid Hervé ; Guillaume Velasco ; Ivan Bieche ; Hélène Buteau-Lozano ; Martine Perrot-Applanat ; Gérard Perret ; Marika Pla

Vascular endothelial growth factor (VEGF) is essential for breast cancer progression and is a relevant target in anti-angiogenesis. Although VEGF121 and VEGF165, the fully or partially secreted isoforms, respectively, have been the focus of intense studies, the role of the cell-associated VEGF189 isoform is not understood. To clarify the contribution of VEGF189 to human mammary carcinogenesis, we established several clones of MDA-MB-231 cells stably overexpressing VEGF189 (V189) and VEGF165 (V165). V189 and V165 clones increased tumor growth and angiogenesis in vivo. Remarkably, V165 induced the most rapid tumor uptake, whereas V189 increased vasodilation. In vitro overexpression of VEGF165 and VEGF189 increases the proliferation and chemokinesis of these cancer cells. Interestingly, overexpression of VEGF189 increased cell adhesion on fibronectin (1.9-fold) and vitronectin (1.6-fold), as compared to VEGF165, through alpha5beta1 and alphavbeta5 integrins. Using the BIACore system we demonstrated for the first time that VEGF189 binds directly to neuropilin-1, which is strongly expressed in MDA-MB-231 cells. In contrast, VEGF-R2 was not significantly expressed and VEGF-R1 was expressed at low level. Our in vitro results suggest an autocrine effect of VEGF189 on breast cancer cells, probably through neuropilin-1. In conclusion, our data indicate that VEGF189 participates in mammary tumor growth through both angiogenesis and nonangiogenic functions. Whether VEGF189 overexpression is correlated to prognosis in human breast tumors remains to be established.

01 Nov 2003·Journal of VirologyQ2 · MEDICINE

Development of Resistance against Diketo Derivatives of Human Immunodeficiency Virus Type 1 by Progressive Accumulation of Integrase Mutations

Q2 · MEDICINE

Article

Author: Debyser, Zeger ; Pannecouque, Christophe ; Van Remoortel, Barbara ; Witvrouw, Myriam ; Michiels, Martine ; Gurnari, Cristina ; De Clercq, Erik ; De Maeyer, Marc ; Van Maele, Bénédicte ; Hantson, Anke ; Engelborghs, Yves ; Fikkert, Valery ; Vercammen, Jo

ABSTRACTThe diketo acid L-708,906 has been reported to be a selective inhibitor of the strand transfer step of the human immunodeficiency virus type 1 (HIV-1) integration process (D. Hazuda, P. Felock, M. Witmer, A. Wolfe, K. Stillmock, J. A. Grobler, A. Espeseth, L. Gabryelski, W. Schleif, C. Blau, and M. D. Miller, Science 287:646-650, 2000). We have now studied the development of antiviral resistance to L-708,906 by growing HIV-1 strains in the presence of increasing concentrations of the compound. The mutations T66I, L74M, and S230R emerged successively in the integrase gene. The virus with three mutations (T66I L74M S230R) was 10-fold less susceptible to L-708,906, while displaying the sensitivity of the wild-type virus to inhibitors of the RT or PRO or viral entry process. Chimeric HIV-1 strains containing the mutant integrase genes displayed the same resistance profile as the in vitro-selected strains, corroborating the impact of the reported mutations on the resistance phenotype. Phenotypic cross-resistance to S-1360, a diketo analogue in clinical trials, was observed for all strains. Interestingly, the diketo acid-resistant strain remained fully sensitive to V-165, a novel integrase inhibitor (C. Pannecouque, W. Pluymers, B. Van Maele, V. Tetz, P. Cherepanov, E. De Clercq, M. Witvrouw, and Z. Debyser, Curr. Biol. 12:1169-1177, 2002). Antiviral resistance was also studied at the level of recombinant integrase. Single mutations did not appear to impair specific enzymatic activity. However, 3′ processing and strand transfer activities of the recombinant integrases with two (T66I L74M) and three (T66I L74M S230R) mutations were notably lower than those of the wild-type integrase. Although the virus with three mutations was resistant to inhibition by diketo acids, the sensitivity of the corresponding enzyme to L-708,906 or S-1360 was reduced only two- to threefold. As to the replication kinetics of the selected strains, the replication fitness for all strains was lower than that of the wild-type HIV-1 strain.

01 Feb 2003·Expert Opinion on Investigational DrugsQ2 · MEDICINE

Dipyrimidine-based inhibitors of HIV-1 integrase

Q2 · MEDICINE

Review

Author: Neamati, Nouri

The extensive sets of in vitro experiments that were performed by Debyser group to demonstrate that the dipyrimidine V-165 is a selective integrase (IN) inhibitor were examinedThe lead compound V-165 and Merck's diketo acid analog L-708,906 showed similar antiviral activity as well as toxicity against HIV-1, HIV-2 and simian immunodeficiency viral-infected MT-4 cells.The 50% effective concentration (EC₅₀) values ranged from 3.7-30 μM, while the 50% cytotoxic concentration value was ∼ 120 μM.V-165 also showed reasonable potency against drug-resistant HIV-1 strains, albeit with twofold reduction in potency with HIV-1 strains resistant against non-nucleoside reverse transcriptase inhibitors.The diketo acid-containing IN inhibitors are reported to be highly selective against strand transfer or integration step of the reaction catalyzed by this enzyme.V-165 is not selective for the strand transfer step of the reaction and also inhibits RT activities with low micromolar.It shows twofold reduced potency against NNRTI-resistant virus.

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Indication	Highest Phase	Country/Location	Organization	Date
HIV Infections	Discovery	BE	Rega Institute for Medical Research	-

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