PubMed Health⌕ Search

Biomedical subjects

Henriette Gourdeau

Publications and source records attributed to Henriette Gourdeau.

10 recordsLinked to original sources
PubMed2004

Action of troxacitabine on cells transduced with human cytidine deaminase cDNA.

Troxacitabine (beta-L-Dioxolane-cytidine; Troxatyl) is a beta-L-nucleoside analog, which has shown preclinical antitumor activity in human xenograft tumor models and antileukemic response in patients with relapsed myeloid leukemia. Troxacitabine is activated by cellular kinases and incorporated into DNA, inhibiting its replication. In contrast to other cytosine nucleoside analogs, troxacitabine is resistant to inactivation by cytidine deaminase (CD). In this study we have investigated the effects of increased intracellular levels of CD on the antineoplastic action of troxacitabine and the related antileukemic drug, cytosine arabinoside (ARA-C). Retroviral transduction of the human CD gene in A549 lung carcinoma cells (A549-CD cells) markedly increased the expression of this gene. The A549-CD cells were more resistant to the cytotoxic action of ARA-C than the wild type A549 cells as determined by clonogenic assays. In contrast, the CD-transduced cells were as or more sensitive to the cytotoxic action of troxacitabine than the wild type cells. These results suggest that troxacitabine may be an effective antineoplastic agent against tumors with high levels of CD that show drug resistance to cytosine nucleoside analogs.

Antineoplastic Agents↗
PubMed2004

Troxacitabine and imatinib mesylate combination therapy of chronic myeloid leukaemia: preclinical evaluation.

The in vitro and in vivo activity of a deoxycytidine analogue, troxacitabine, alone or in combination with imatinib mesylate (IM), was evaluated against human chronic myeloid leukaemia (CML) cell lines both sensitive (KBM5 and KBM7) and resistant (KBM5-R and KBM7-R) to IM. These cell lines differ in their sensitivity to IM but all showed similar sensitivity to treatment with troxacitabine (IC50 = 0.5-1 micromol/l). Combined treatment with troxacitabine and IM revealed additive or synergistic effects. Greater apoptotic response was seen with combined treatment than with either agent alone in KBM7-R cells. In clonogenic assays, troxacitabine showed activity against mononuclear cells from CML patients (IC50 = 0.01 micromol/l) with either IM-sensitive or resistant disease. In vivo efficacy studies were carried out in severe combined immunodeficient mice bearing KBM5 or KBM5-R cells. Troxacitabine was administered i.p. daily for 5 d starting on day 20, at doses of 5, 10, 20, or 25 mg/kg. IM was administered i.p. twice a day for 10 d at a dose of 50 mg/kg starting on day 25. In this setting of late stage disease, troxacitabine led to a significant increase in life span, while IM did not. When IM was combined with troxacitabine at 10 and 25 mg/kg in the KBM5 xenograft model, a further increase in life span was observed and some mice achieved long-term survival. These data indicate that the combination of troxacitabine and IM has significant preclinical activity in advanced CML and that clinical evaluation of this combination is warranted.

Animals↗
PubMed2004

[Troxacitabine].

Nucleoside analogues are commonly used in the treatment of hematological malignancies and solid tumors. As antimetabolites, these drugs act by disrupting DNA synthesis and inducing apoptosis following their incorporation into DNA. Troxacitabine (Troxatyl) is the first nucleoside analogue with anticancer activity that has an unnatural stereochemical configuration. Its broad preclinical antineoplastic spectrum led to its clinical development. Summaries of the preclinical data and of the initial phase I and II clinical trials are presented.

Acute Disease↗
PubMed2004

Discovery and mechanism of action of a novel series of apoptosis inducers with potential vascular targeting activity.

A novel series of 2-amino-4-(3-bromo-4,5-dimethoxy-phenyl)-3-cyano-4H-chromenes was identified as apoptosis-inducing agents through our cell-based apoptosis screening assay. Several analogues from this series, MX-58151, MX-58276, MX-76747, MX-116214, MX-126303, and MX-116407, were synthesized and further characterized. MX-116407, a lead compound from this series, induced apoptosis with an EC50 of 50 nmol/L and inhibited cell growth with a GI50 of 37 nmol/L in T47D breast cancer cells. Treatment of cells with these analogues led to G2-M arrest, cleavage of essential proapoptotic caspase substrates, and induction of nuclear fragmentation. We identified these compounds as tubulin destabilizers with binding site at or close to the colchicine binding site. Compounds in this series were also active in drug-resistant cancer cell lines with a GI50 value for one of the analogues (MX-58151) of 2.5 nmol/L in paclitaxel-resistant, multidrug-resistant MES-SA/DX5 tumor cells. This series of compounds displayed high selectivity against proliferating versus resting cells. Interestingly, these compounds were shown to disrupt preformed endothelial cell capillary tubules in vitro and affect functional vasculature to induce tumor necrosis in vivo and are thus likely to work as tumor vasculature targeting agents. Among these compounds, MX-116407 showed capillary tubule disruption activity in vitro at concentrations well below the cytotoxic dose. In a separate study, we further characterized the antitumor efficacy and pharmacokinetic profile of this series of compounds and identified MX-116407 as a potent apoptosis-inducing agent with apparent activity as tumor vasculature targeting agent.

Antineoplastic Agents↗
PubMed2004

Antivascular and antitumor evaluation of 2-amino-4-(3-bromo-4,5-dimethoxy-phenyl)-3-cyano-4H-chromenes, a novel series of anticancer agents.

A novel series of 2-amino-4-(3-bromo-4,5-dimethoxy-phenyl)-3-cyano-4H-chromenes was identified as potent apoptosis inducers through a cell-based high throughput screening assay. Six compounds from this series, MX-58151, MX-58276, MX-76747, MX-116214, MX-116407, and MX-126303, were further profiled and shown to have potent in vitro cytotoxic activity toward proliferating cells only and to interact with tubulin at the colchicine-binding site, thereby inhibiting tubulin polymerization and leading to cell cycle arrest and apoptosis. Furthermore, these compounds were shown to disrupt newly formed capillary tubes in vitro at low nanomolar concentrations. These data suggested that the compounds might have vascular targeting activity. In this study, we have evaluated the ability of these compounds to disrupt tumor vasculature and to induce tumor necrosis. We investigated the pharmacokinetic and toxicity profiles of all six compounds and examined their ability to induce tumor necrosis. We next examined the antitumor efficacy of a subset of compounds in three different human solid tumor xenografts. In the human lung tumor xenograft (Calu-6), MX-116407 was highly active, producing tumor regressions in all 10 animals. Moreover, MX-116407 significantly enhanced the antitumor activity of cisplatin, resulting in 40% tumor-free animals at time of sacrifice. Our results identify MX-116407 as the lead candidate and strongly support its continued development as a novel anticancer agent for human use.

Amination↗
PubMed2003

Complementary antineoplastic activity of the cytosine nucleoside analogues troxacitabine (Troxatyl) and cytarabine in human leukemia cells.

PURPOSE: Troxacitabine (BCH-4556, l-(-)-OddC, Troxatyl) is a novel beta- l-nucleoside analogue with potent antineoplastic activity both in vitro and in several tumor models in vivo, and is presently in phase II clinical trials. The combination of the cytosine analogues troxacitabine and araC (1-beta- d-arabinofuranosylcytosine, cytarabine) has shown promising activity in patients with acute myelogenous leukemia. To further examine the interactions between these two analogues, we investigated the in vitro and in vivo effects of their combination against a human leukemia cell line, CCRF-CEM. METHODS: . The in vitro cytotoxic effect of the combination of troxacitabine and araC on the survival of CCRF-CEM cells was measured using a standard MTT assay and combination indices were generated with the CalcuSyn software. For in vivo studies, we evaluated the effect of both drugs, alone and in combination, on survival of CCRF-CEM tumor-bearing animals. Mechanistic studies addressed recovery of DNA synthesis, intracellular levels of araC metabolites, feedback inhibition by triphosphate species and pharmacokinetics of both drugs. RESULTS: The combination of troxacitabine and araC in vitro was synergistic with combination indices between 0.1 and 0.7. This appeared to be related to the impact of the combination on DNA synthesis recovery, which was significantly delayed following exposure to the combination of troxacitabine and araC compared to either agent alone. Analysis of the effect of troxacitabine on the intracellular metabolites of araC revealed that troxacitabine did not inhibit araC deamination and caused a slight decrease in the overall intracellular accumulation of araCTP. The lower accumulation of araCTP could not be attributed to feedback inhibition caused by troxacitabine triphosphate on dCK. Furthermore, our in vivo experiments demonstrated that the combination of araC and troxacitabine was better at slowing down the progression of leukemia in SCID mice than either agent used alone without additive toxicities. Injections of 10 mg/kg troxacitabine i.p. daily for 5 days in combination with araC at 10 mg/kg led to an increase in median survival time of 58 days compared to 49.5 and 53.5 days for araC and troxacitabine, respectively, given as single agents. This represents an increase in life span of 17%, respectively when compared to araC alone. A pharmacokinetic study revealed that troxacitabine did not influence the disposition of araC when coadministered. CONCLUSIONS: Overall, our results show that the antileukemic activity of troxacitabine and araC is complementary when the two nucleoside analogues are combined in vivo. These effects appear to be related to their interaction at the level of DNA repair rather than to pharmacokinetic interactions. These results encourage the use of troxacitabine and araC in combination in patients with acute leukemia.

Animals↗
PubMed2003

A novel RGD antagonist that targets both alphavbeta3 and alpha5beta1 induces apoptosis of angiogenic endothelial cells on type I collagen.

Integrin-mediated cell adhesion is necessary for endothelial cell proliferation and apoptosis, which is a major determinant in tumor-induced angiogenesis. In this study, we compared two novel, structurally similar, Arg-Gly-Asp (RGD) peptidomimetic compounds having different integrin selectivities, for their inhibition of endothelial cell proliferation and induction of apoptosis on functionally relevant extracellular matrices (ECM) for angiogenesis. BCH-14661 was specific for integrin alphavbeta3, whereas BCH-15046 nonselectively antagonized integrins alphavbeta3, alphavbeta5, and alpha5beta1. Both compounds were potent inducers of endothelial cell apoptosis when plated on RGD-dependent ECM (vitronectin, VN), which was dependent on the ability to induce cell detachment. However, with endothelial cells plated on RGD-independent ECM (type I collagen, COL), only BCH-15046 was able to significantly prevent growth and induce apoptosis. This effect was not dependent on the induction of detachment. Experiments using the matrix metalloproteinase (MMP) inhibitor GM 6001 revealed that cleavage of COL was not required for the ability of BCH-15046 to induce apoptosis. However, the inhibition of growth factor-stimulated endothelial cell proliferation, required MMPs, and correlated with BCH-15046s' potent inhibition of endothelial cell attachment to denatured collagen. Antibody inhibition experiments showed that adhesion to denatured collagen required integrins alphavbeta3 and beta1, but not alphavbeta5. In addition, BCH-15046 exerted a significant inhibition of VEGF-stimulated angiogenesis in the chick chorioallontoic membrane in vivo. These results suggest that integrin antagonism of both alphavbeta3 and alpha5beta1 are important for MMP-independent induction of apoptosis on COL and MMP-dependent inhibition of endothelial cell-denatured collagen interactions required for proliferation.

Anoikis↗
PubMed2002

Antitumor activity of troxacitabine (Troxatyl) against anthracycline-resistant human xenografts.

PURPOSE: We have recently identified a deoxycytidine nucleoside analogue, troxacitabine (beta- L-dioxolane cytidine, Troxatyl; Shire BioChem), which has potent antitumor activity against both leukemia and solid tumors. In contrast to the cytidine nucleoside analogues currently in clinical use (cytarabine and gemcitabine), troxacitabine is a poor substrate of nucleoside transporters and enters cells primarily by passive diffusion. This unusual property led us to evaluate the efficacy of troxacitabine in multidrug resistant (MDR) and multidrug resistance-associated protein (MRP) tumors. METHODS: The in vitro antiproliferative activity of troxacitabine was investigated in the human nasopharyngeal epidermoid carcinoma cell line, KB, and its vincristine-resistant derivative (KBV), as well as in human leukemia cell lines of myeloid and lymphoblastoid origin, HL60 and CCRF-CEM, respectively, and their MDR (HL60/R10 and CCRF-CEM/VLB) and MRP (HL60/ADR) derivatives, using the thymidine incorporation assay. For in vivo studies, we compared the antitumor efficacy of troxacitabine with that of doxorubicin and vinblastine in xenograft models of these solid and hematological human anthracycline-resistant tumor xenografts. RESULTS: Troxacitabine demonstrated potent antiproliferative activity against both P-glycoprotein-positive (KBV, HL60/R10, CCRF-CEM/VLB) and P-glycoprotein-negative (HL60/ADR) multidrug-resistant cell lines with IC(50) values ranging from 7 to 171 n M. Tumor regression was observed in the KBV xenograft following a 5-day treatment with 20, 50 and 100 mg/kg of troxacitabine, with percent total growth inhibition (TGI) of 81, 96 and 97, respectively, and some cures at the two highest dose levels. In the HL60, HL60/R10, HL60/ADR and CCRF-CEM/VLB xenografts, the effect of troxacitabine was evaluated on survival time. In the HL60 promyelocytic human xenograft models, troxacitabine treatment (25, 50 and 100 mg/kg per day for 5 days) was initiated 10 days after tumor cell inoculation, once animals had developed disseminated tumors. In all three promyelocytic leukemia xenografts, troxacitabine was quite potent, producing T/C values of 162% to 315% as well as complete cures at the higher dose levels. In the CCRF-CEM/VLB T-lymphoblastoid leukemia xenograft, troxacitabine treatment (10, 30 or 250 mg/kg total doses using different schedules) was initiated 20 days after tumor cell inoculation. Troxacitabine was not as potent in this model but did result in significant antileukemic activity (T/C of 131%) when administered at 10 mg/kg on days 20, 27 and 34. CONCLUSIONS: These results indicate that troxacitabine has a potent in vivo antitumor activity associated with tumor regressions and complete cures in animals with tumors refractory to current chemotherapeutic agents.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2002

BCH-1868 [(-)-2-R-dihydroxyphosphinoyl-5-(S)-(guanin-9'-yl-methyl) tetrahydrofuran]: a cyclic nucleoside phosphonate with antitumor activity.

Nucleoside phosphonates are widely used therapeutic agents with a broad spectrum of antiviral activity. However, only a few of them are reported to have antitumor activity. In this study, we show that a tetrahydrofuran phosphonate analogue of guanosine, (-)-2-R-dihydroxyphosphinoyl-5-(S)-(guanin-9'-ylmethyl) tetrahydrofuran (BCH-1868), previously reported as having antiviral activity, also displays antitumor activity. In vitro, BCH-1868 inhibited the proliferation of several murine and human cancer cell lines with IC50s in the microM range independently of the tissue type or the presence of multidrug resistance protein MRP/gp190. In vivo, BCH-1868 was active against a variety of human tumor xenograft models (Caki-1, HT-29, DU 145, COLO 205, and CCRF-CEM). In all tumors tested, a significant tumor growth inhibition was noted at 40-50 mg/kg (daily x 5), but no tumor regression was observed in the settings used. To better understand these results, we partially characterized, at the cellular level, the mechanism of action of this new cyclic nucleoside phosphonate and investigated its pharmacokinetic characteristics in mice. We showed that BCH-1868 exerts its antitumor activity by an inhibitory mechanism at the level of DNA polymerase a, resulting in arrest of DNA synthesis and a block of cell division at the S phase of the cell cycle. Low-circulating plasma concentration (Cmax = 87 microM; area under the curve = 1138 micromol x min/liters; after a bolus i.v. injection of 10 mg/kg) and rapid clearance of the drug (terminal half-life, t1/2 = 16 min) may contribute to the modest antitumor efficacy observed in vivo.

Animals↗