vinflunine and Colonic-Neoplasms

Vinflunine is a new Vinca alkaloid uniquely fluorinated, by the use of superacid chemistry, in a little exploited region of the catharanthine moiety. In vitro investigations have confirmed the mitotic-arresting and tubulin-interacting properties of vinflunine shared by other Vinca alkaloids. However, differences in terms of the inhibitory effects of vinflunine on microtubules dynamics and its tubulin binding affinities have been identified which appear to distinguish it from the other Vinca alkaloids. Vinflunine induced smaller spirals with a shorter relaxation time, effects, which might be associated with reduced neurotoxicity. Studies investigating the in vitro cytotoxicity of vinflunine in combination therapy have revealed a high level of synergy when vinflunine was combined with either cisplatin, mitomycin C, doxorubicin or 5-fluorouracil. Furthermore, although vinflunine appears to participate in P-glycoprotein-mediated drug resistance mechanisms, it has proved only a weak substrate for this protein and a far less potent inducer of resistance than vinorelbine. Vinflunine was identified in preclinical studies as having marked antitumour activity in vivo against a large panel of experimental tumour models, with tumour regressions being recorded in human renal and small cell lung cancer tumour xenografts. Overall its level of activity was superior to that of vinorelbine in many of the experimental models used. Interestingly, an in vivo study using a well vascularised adenocarcinoma of the colon has suggested that vinflunine mediates its antitumour activity at least in part via an antivascular mechanism, even at sub-cytotoxic doses. Therefore, these data provide a favourable preclinical profile for vinflunine, supporting its promising candidacy for clinical development. Phase I evaluations of vinflunine have been completed in Europe and phase II clinical trials are now ongoing.

Topics: Adenocarcinoma; Angiogenesis Inhibitors; Animals; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line; Colonic Neoplasms; DNA Damage; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Forecasting; Humans; Leukemia P388; Lung Neoplasms; Melanoma, Experimental; Mice; Microtubules; Molecular Structure; Neoplasms, Experimental; Nervous System Diseases; Tubulin Modulators; Tumor Cells, Cultured; Vinblastine; Vinca Alkaloids; Xenograft Model Antitumor Assays

Chemotherapy drugs usually inflict a lethal dose to tumour cells with the consequence that these cells are being killed by cell death. However, each round of chemotherapy also causes damage to normal somatic cells. The DNA cross-linking agent oxaliplatin (OXP), which causes DNA double-strand breaks, and vinflunine (VFN), which disrupts the mitotic spindle, are two of these chemotherapy drugs which were evaluated in vitro using peripheral lymphocytes from colorectal cancer patients and healthy individuals to determine any differential response. Endpoints examined included micronucleus (MN) induction using the cytokinesis-blocked micronucleus (CBMN) assay and pancentromeric fluorescence in situ hybridisation. Also, survivin expression was monitored since it regulates the mitotic spindle checkpoint and inhibits apoptosis. OXP produced cytogenetic damage (micronuclei in binucleated cells) via its clastogenic but also previously unknown aneugenic action, possibly through interfering with topoisomerase II, whilst VFN produced micronuclei in mononucleated cells because of incomplete karyokinesis. Survivin expression was found to be significantly reduced in a concentration-dependent manner by not only OXP but surprisingly also VFN. This resulted in large numbers of multinucleated cells found with the CBMN assay. As survivin is upregulated in cancers, eliminating apoptosis inhibition might provide a more targeted chemotherapy approach; particularly, when considering VFN, which only affects cycling cells by inhibiting their mitotic spindle, and alongside possibly other pro-apoptotic compounds. Hence, these newly found properties of VFN -the inhibition of survivin expression-might demonstrate a promising chemotherapeutic approach as VFN induces less DNA damage in normal somatic cells compared to other chemotherapeutic compounds.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Gene Expression Regulation; Humans; In Situ Hybridization, Fluorescence; Inhibitor of Apoptosis Proteins; Lymphocytes; Male; Micronuclei, Chromosome-Defective; Micronucleus Tests; Mutagens; Organoplatinum Compounds; Oxaliplatin; Survivin; Vinblastine

The aim of this study was to investigate the anti-angiogenic, vascular-disrupting and anti-metastatic properties of vinflunine, the latest vinca alkaloid in phase III clinical development. The effects of vinflunine on in vitro endothelial cell functions relevant to the performance of an already formed vasculature and to the angiogenic process were evaluated. The in vivo anti-angiogenic properties of vinflunine were also investigated, as were its activity against a model of experimental metastasis. In vitro vinflunine induced a rapid change in the morphology of endothelial cells and disrupted the network of capillary-like structures, indicating potential vascular-disrupting activity. Furthermore, vinflunine showed anti-angiogenic properties, since it inhibited endothelial cell migration and the capacity of these cells to organise into a network of capillary-like structures. All these effects were observed under conditions that only marginally affect endothelial cell proliferation. In vivo, vinflunine inhibited bFGF-induced angiogenesis in Matrigel implants at doses 40-20-fold lower than its maximal therapeutic dose (MTD). Treatment of mice with vinflunine reduced the number of liver metastases induced by intrasplenic injection of LS174T cells, with significant effects also observed at low doses; i.e. 16-fold lower than the MTD. This study demonstrates that vinflunine expresses both vascular-disrupting and anti-angiogenic activities and induced marked effects against experimental metastases, all properties that support its ongoing clinical development.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Colonic Neoplasms; Female; Liver Neoplasms; Mice; Mice, Inbred C57BL; Microtubules; Neovascularization, Pathologic; Tumor Cells, Cultured; Vinblastine; Vinca Alkaloids