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Paul E. Goss - One of the best experts on this subject based on the ideXlab platform.

  • Effects of Liarozole fumarate (R85246) in combination with tamoxifen on N-methyl-N-nitrosourea (MNU)-induced mammary carcinoma and uterus in the rat model.
    BMC cancer, 2007
    Co-Authors: Paul E. Goss, Kathrin Strasser-weippl
    Abstract:

    Background Liarozole fumarate (Liarozole – R85246) is a novel compound with characteristics of both aromatase inhibitor (AI) and a retinoic acid metabolism blocking agent (RAMBA). Our objective was to determine the effects of Liarozole alone or in combination with tamoxifen on the N-methyl-N-nitrosourea (MNU)-induced rat mammary carcinoma model, as well as on the uterus in ovariectomized immature rats.

  • Liarozole Fumarate (R85246): In the Treatment of ER Negative, Tamoxifen Refractory or Chemotherapy Resistant Postmenopausal Metastatic Breast Cancer
    Breast Cancer Research and Treatment, 2000
    Co-Authors: Paul E. Goss, Rakesh Goel, Kathrin Strasser, Ricardo Marques, Mark Clemons, Amit Oza, Martin Blackstein, Leonard Kaizer, Ernest E. Sterns, Jeanmarc Nabholtz
    Abstract:

    Three phase II studies were conducted to determine the efficacy and tolerability of Liarozole fumarate (R85246; Liarozole), a retinoic acid metabolism blocking agent (RAMBA) and aromatase inhibitor. Additionally, animal experiments in the MNU-induced rat mammary tumor model and in immature ovariectomized rats were conducted to further elucidate Liarozole's mechanisms of action. Patients were postmenopausal with either: ER negative disease in first relapse (Group 1; n  = 16); ER positive or unknown disease refractory to tamoxifen (Group 2; n  = 16); ER positive, negative or unknown disease resistant or refractory to chemotherapy (Group 3; n  = 27). Treatment was Liarozole (150–300 mg) twice daily orally until disease progression. Response rates were: 25% in group 1 (95% CI 11.0–52.3%; median duration (MD) 20 months; range 2–36.5); 25% in group 2 (95% CI 11.0–52.3%; MD 6.5 months; range 3.5–38); 11% in group 3 (95% CI 4.2–29.2%; MD 7 months; range 3–8.5). No significant improvement in quality of life scores (FLI-C) was noted. Toxicities observed were predominantly dermatological (skin disorders: 88%; dry mouth/eyes/lips: 69%). Plasma estradiol decreased from mean pre-treatment levels of 72.7 pM (9.1–1839 pM) to below detection (9.2 pM) after 1 month. Liarozole, but not vorozole, partially inhibited estradiol induced uterine hypertrophy and demonstrated dose-dependent anti-tumor effects in the rats, only partially overcome by coadministration of estradiol. The clinical responses observed, together with our preclinical results, confirm Liarozole's dual mechanism of action and provide a rationale for further evaluation of RAMBAs in the treatment of breast cancer.

  • Liarozole fumarate r85246 a novel imidazole in the treatment of receptor positive postmenopausal metastatic breast cancer
    Breast Cancer Research and Treatment, 2000
    Co-Authors: Paul E. Goss, J Bruynseels, Roland De Coster, Amit M Oza, Rakesh Goel, Jeanmarc Nabholtz, Caroline Reid, Nancy Wadden, Michael Crump, L M Tye
    Abstract:

    This phase II study of Liarozole fumarate (R85246, Liarozole), a novel imidazole with retinomimetic and aromatase inhibitory effects, was designed to determine the efficacy and tolerability in postmenopausal women with advanced breast cancer in progression, to correlate these effects with hormonal levels, and to evaluate quality of life. Twenty-nine women with ER-positive or unknown metastatic disease who received ≥ 2 prior hormonal therapies were treated with 150–300 mg Liarozole twice daily until disease progression. All patients were evaluable for toxicity and 25 for response. Four patients (16.0%, 95% CI 5.3–37.4%) had partial remission (PR) of their disease for a median of 7.4 months (range 1.2–12.9) and 7 (28%) had disease stabilization for a median of 4.8 months (1.6–16.0). Estradiol decreased from pre-treatment levels of 9.2–52 pM (mean 17.1) to below detection (9.2 pM, p=0.0005) after 1 month. Similarly estrone levels fell from 14–307 pM (mean 92.7) to below detection (9.2 pM, p=0.0001). The most common toxicity was dermatological (96.6%) with features compatible with hypervitaminosis A syndrome such as rash, pruritus, dry skin, and brittle nails. The majority of these were mild to moderate in severity. No significant improvement in quality of life scores (FLI-C) were noted. Liarozole is an active new treatment for breast cancer in patients heavily pre-treated with hormone therapies. Further studies are needed to confirm its relative efficacy in both receptor positive and negative postmenopausal breast cancer.

Anders Vahlquist - One of the best experts on this subject based on the ideXlab platform.

  • oral Liarozole in the treatment of patients with moderate severe lamellar ichthyosis results of a randomized double blind multinational placebo controlled phase ii iii trial
    British Journal of Dermatology, 2014
    Co-Authors: Anders Vahlquist, S Blockhuys, P M Steijlen, K Van Rossem, B Didona, D Blanco, Heiko Traupe
    Abstract:

    Summary Background Oral Liarozole, a retinoic acid metabolism-blocking agent, may be an alternative to systemic retinoid therapy in patients with lamellar ichthyosis. Objective To demonstrate the efficacy and safety of once-daily oral Liarozole in the treatment of moderate/severe lamellar ichthyosis. Methods This was a double-blind, multinational, parallel phase II/III trial (NCT00282724). Patients aged ≥ 14 years with moderate/severe lamellar ichthyosis [Investigator's Global Assessment (IGA) score ≥ 3] were randomized 3 : 3 : 1 to receive oral Liarozole (75 or 150 mg) or placebo once daily for 12 weeks. Assessments included: IGA; a five-point scale for erythema, scaling and pruritus severity; Short Form-36 health survey; Dermatology Life Quality Index (DLQI); and safety parameters. The primary efficacy variable was response rate at week 12 (responder: ≥ 2-point decrease in IGA from baseline). Results Sixty-four patients were enrolled. At week 12, 11/27 (41%; Liarozole 75 mg), 14/28 (50%; Liarozole 150 mg) and one out of nine (11%; placebo) patients were responders; the difference between groups (Liarozole 150 mg vs. placebo) was not significant (P = 0·056). Mean IGA and scaling scores decreased from baseline in both Liarozole groups at weeks 8 and 12 vs. placebo; erythema and pruritus scores were similar between treatment groups. Improvement in DLQI score was observed in both Liarozole groups. Treatment with Liarozole for 12 weeks was well tolerated. Conclusions The primary efficacy variable did not reach statistical significance, possibly owing to the small sample size following premature termination. However, once-daily oral Liarozole, 75 and 150 mg, improved scaling and DLQI and was well tolerated in patients with moderate/severe lamellar ichthyosis.

  • Funding sources
    2013
    Co-Authors: Anders Vahlquist
    Abstract:

    Oral Liarozole in the treatment of patients with moderate/severe lamellar ichthyosis: results of a randomized, double-blind, multinational, placebo-controlled phase II/III tria

  • expression of retinoid regulated genes in lamellar ichthyosis vs healthy control epidermis changes after oral treatment with Liarozole
    Acta Dermato-venereologica, 2009
    Co-Authors: Elizabeth Pavez Lorie, Agneta Ganemo, Marcel Borgers, Luc Wouters, Stan Blockhuys, Lieve Van De Plassche, Hans Torma, Anders Vahlquist
    Abstract:

    Lamellar ichthyosis is a keratinization disorder caused by TGM1, Ichthyin and several other gene mutations. A new treatment option is Liarozole, which blocks the cytochrome P450 (CYP26)-mediated catabolism of endogenous all-trans retinoic acid. This study focuses on the expression of retinoid-related genes in ichthyotic epidermis before and after treatment with oral Liarozole. We first compared the mRNA expression of cellular retinoic acid binding protein II (CRABPII), keratin (KRT) 2 and 4, CYP26A1 and B1, and two markers of inflammation (interleukin-1alpha and tumours necrosis factor (TNF)-alpha) in shave biopsies from 11 genetically defined, untreated patients and 12 age- and sex-matched healthy controls, finding no overt differences between the groups, besides elevated CRABPII expression. We then studied the biomarkers before and after 4 weeks of treatment with Liarozole (75 or 150 mg/day), which produced a better therapeutic response in patients with Ichthyin (n=3) than in those with TGM1 (n=6) mutations. A significant decrease in the mRNA expression of KRT2 and TNF-alpha, and trends toward increased expression of KRT4 and CYP26A1 were observed in Liarozole-treated patients, consistent with an increased retinoid stimulation of epidermis. However, there were no dose-related responses and the results of the immunostaining did not always parallel the mRNA findings. The results suggest that Liarozole exerts a therapeutic effect in lamellar ichthyosis by mildly affecting the expression of retinoid- regulated genes in epidermis.

R De Coster - One of the best experts on this subject based on the ideXlab platform.

  • Liarozole potentiates the all trans retinoic acid induced structural remodelling in human breast carcinoma mcf 7 cells in vitro
    European Journal of Cell Biology, 1996
    Co-Authors: J Van Heusden, W Wouters, R De Coster, F C S Ramaekers, M Borgers, B Xhonneux, G Smets
    Abstract:

    Liarozole inhibits cytochrome P-450-dependent enzymes that play a key role in all-trans-retinoic acid (ATRA) catabolism. In MCF-7 cells, Liarozole potentiates the antiproliferative effects of ATRA. The present study demonstrates this synergistic effect on cell differentiation of MCF-7 cell cultures as measured by immunocytochemistry for cytokeratins 8, 18, and 19, actin, E-cadherin, desmoglein and desmoplakins I & II. ATRA concentration-dependently (10(-8) M-10(-6) M) induced changes in actin stress fibers and cytokeratin intermediate filaments. These changes were accompanied by a more obvious interaction of these filaments with junctional complexes. Surface area and volume of the MCF-7 cells increased markedly after ATRA exposure, with extensive filopodia formation. Liarozole (10(-6) M) alone had no effect on cell morphology, cytokeratin or actin organization, or on cellular junctions. In combination with ATRA (10(-9) M and 10(-8) M), Liarozole potentiated the ATRA-induced effects. The MCF-7 cell cultures used showed morphological heterogeneity, consisting of at least two cellular subpopulations. This was reflected in the staining for E-cadherin, desmoglein and desmoplakins I & II. ATRA increased E-cadherin staining at cell-cell contact sites, but had no influence on the staining patterns of desmoglein and desmoplakins I & II. Similar to what has been observed for the cytoskeletal differentiation parameters, Liarozole alone had no influence on E-cadherin, desmoglein or desmoplakins I & II expression, but in combination with ATRA again intensified the effects on E-cadherin distribution. These effects on MCF-7 cells agree with previously obtained observations concerning the inhibition of ATRA catabolism by Liarozole. Furthermore, our data support the hypothesis that the antiproliferative properties of the drug are accompanied by induction of differentiation.

  • Liarozole an antitumor drug modulates cytokeratin expression in the dunning at 6sq prostatic carcinoma through in situ accumulation of all trans retinoic acid
    The Prostate, 1995
    Co-Authors: G Smets, J Van Wauwe, M C Coene, J A Schalken, R Van Ginckel, M Borgers, G Daneels, M Moeremans, Frans C S Ramaekers, R De Coster
    Abstract:

    Liarozole showed antitumoral activity in the Dunning AT-6sq, an androgen-independent rat prostate carcinoma. To investigate its potential mechanism of action, the effects of the drug doses (ranging from 3.75 to 80 mg/kg b.i.d.) on endogenous plasma and tissue all-trans-retinoic acid levels and on the differentiation status of the tumor cells were evaluated. To follow modulation of differentiation, cytokeratins were localized in the (un)treated tumors by immunocytochemistry and quantitatively determined by immunoblotting. Results showed that Liarozole statistically significantly reduced tumor weight from 30 mg/kg upwards and induced accumulation of all-trans-retinoic acid both in plasma and tumors. In the tumors, a statistically significant accumulation was already noted from 7.5 mg Liarozole/kg upwards. Concomitantly, the differentiation status shifted from a keratinizing towards a non-keratinizing squamous carcinoma, which was further confirmed by the cytokeratin profile of the carcinoma (presence of CK 8, 10, 13, 14, 18, 19). Immunoblotting revealed an overall decrease in cytokeratin content, except for CK 8. These findings suggest that the antitumoral properties of Liarozole might be related to an increase in the degree of tumor differentiation through accumulation of all-trans-retinoic acid.

  • experimental studies with Liarozole r 75 251 an antitumoral agent which inhibits retinoic acid breakdown
    The Journal of Steroid Biochemistry and Molecular Biology, 1992
    Co-Authors: R De Coster, M C Coene, W Wouters, R Van Ginckel, David W End, M D W G Krekels, C Bowden
    Abstract:

    Abstract Liarozole reduced tumor growth in the androgen-dependent Dunning-G and the androgen-independent Dunning MatLu rat prostate carcinoma models as well as in patients with metastatic prostate cancer who had relapsed after orchiectomy. In vitro , Liarozole did not have cytostatic properties, as measured by cell proliferation in breast MCF-7 and prostate DU145 and LNCaP carcinoma cell lines. It did not alter the metabolism of labeled testosterone i.e. the 5α-reductase in cultured rat prostatic cells. In mouse F9 teratocarcinoma cells Liarozole did not show any retinoid-like properties but enhanced the plasminogen activator production induced by retinoic acid. Furthermore, Liarozole and retinoic acid similarly reduced the growth of the androgen-dependent Dunning-G tumor in nude mice and inhibited tumor promotion elicited by phorbol ester in mouse skin. These data have raised the hypothesis that the antitumoral properties of Liarozole may be related to inhibition of retinoic acid degradation, catalyzed by a P -450-dependent enzyme that is blocked by the drug.

  • effects of Liarozole a new antitumoral compound on retinoic acid induced inhibition of cell growth and on retinoic acid metabolism in mcf 7 human breast cancer cells
    Cancer Research, 1992
    Co-Authors: W Wouters, M C Coene, W Cools, J Van Dun, A Dillen, R De Coster
    Abstract:

    Liarozole is a new imidazole derivative with antitumoral properties. Effects of the compound alone and in combination with all-trans-retinoic acid on proliferation of MCF-7 human breast cancer cells were examined using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assay. Following 9 days of drug exposure, MCF-7 cell growth was concentration dependently inhibited by all-trans-retinoic acid (drug concentration resulting in 50% growth inhibition, 2 x 10(-8) M), while Liarozole at 10(-5) M inhibited cell growth by only 35%. When MCF-7 cells were incubated with a combination of all-trans-retinoic acid and Liarozole, the antiproliferative effect of all-trans-retinoic acid was clearly enhanced. This enhancement was dependent on the Liarozole concentration and was more than 10-fold. A combination of 10(-8) M all-trans-retinoic acid and 10(-6) M Liarozole resulted in a greater antiproliferative effect than that obtained with 10(-7) M all-trans-retinoic acid alone. When MCF-7 cells were incubated for 4 h with [3H]all-trans-retinoic acid, the radioactivity in the supernatant consisted of unaltered retinoid. However, when cells had been pretreated with 10(-6) M all-trans-retinoic acid overnight, they were able to substantially metabolize [3H]all-trans-retinoic acid during a subsequent 4-h incubation. High-performance liquid chromatography analysis of the supernatants revealed that the reaction products consisted mainly of very polar metabolites. Liarozole inhibited the metabolism of all-trans-retinoic acid in MCF-7 cells with 10(-5) M Liarozole reducing the amount of polar metabolites by 87%. It is concluded that the enhancement by Liarozole of the antiproliferative effects of retinoic acid on MCF-7 human breast cancer cells is probably due to inhibition of retinoic acid metabolism. Further research into these effects in MCF-7 cells as well as in other cancer cell lines will provide more information concerning the exact mechanism of action of Liarozole and the use of inhibitors of retinoid metabolism in cancer treatment.

P M Steijlen - One of the best experts on this subject based on the ideXlab platform.

  • oral Liarozole in the treatment of patients with moderate severe lamellar ichthyosis results of a randomized double blind multinational placebo controlled phase ii iii trial
    British Journal of Dermatology, 2014
    Co-Authors: Anders Vahlquist, S Blockhuys, P M Steijlen, K Van Rossem, B Didona, D Blanco, Heiko Traupe
    Abstract:

    Summary Background Oral Liarozole, a retinoic acid metabolism-blocking agent, may be an alternative to systemic retinoid therapy in patients with lamellar ichthyosis. Objective To demonstrate the efficacy and safety of once-daily oral Liarozole in the treatment of moderate/severe lamellar ichthyosis. Methods This was a double-blind, multinational, parallel phase II/III trial (NCT00282724). Patients aged ≥ 14 years with moderate/severe lamellar ichthyosis [Investigator's Global Assessment (IGA) score ≥ 3] were randomized 3 : 3 : 1 to receive oral Liarozole (75 or 150 mg) or placebo once daily for 12 weeks. Assessments included: IGA; a five-point scale for erythema, scaling and pruritus severity; Short Form-36 health survey; Dermatology Life Quality Index (DLQI); and safety parameters. The primary efficacy variable was response rate at week 12 (responder: ≥ 2-point decrease in IGA from baseline). Results Sixty-four patients were enrolled. At week 12, 11/27 (41%; Liarozole 75 mg), 14/28 (50%; Liarozole 150 mg) and one out of nine (11%; placebo) patients were responders; the difference between groups (Liarozole 150 mg vs. placebo) was not significant (P = 0·056). Mean IGA and scaling scores decreased from baseline in both Liarozole groups at weeks 8 and 12 vs. placebo; erythema and pruritus scores were similar between treatment groups. Improvement in DLQI score was observed in both Liarozole groups. Treatment with Liarozole for 12 weeks was well tolerated. Conclusions The primary efficacy variable did not reach statistical significance, possibly owing to the small sample size following premature termination. However, once-daily oral Liarozole, 75 and 150 mg, improved scaling and DLQI and was well tolerated in patients with moderate/severe lamellar ichthyosis.

  • oral Liarozole vs acitretin in the treatment of ichthyosis a phase ii iii multicentre double blind randomized active controlled study
    British Journal of Dermatology, 2007
    Co-Authors: Christel J Verfaille, F P Vanhoutte, C Blanchetbardon, M A M Van Steensel, P M Steijlen
    Abstract:

    Summary Background  Liarozole, a retinoic acid metabolism blocking agent, has been granted orphan drug status for congenital ichthyosis by the European Commission and the U.S. Food and Drug Administration. Objectives  The purpose of this trial was to investigate the efficacy, tolerability and safety of oral Liarozole vs. acitretin in patients with ichthyosis. Methods  In this double-blind comparative trial of Liarozole vs. acitretin, 32 patients with ichthyosis were randomized to be treated with either oral Liarozole 75 mg in the morning and 75 mg in the evening or with acitretin 10 mg in the morning and 25 mg in the evening for 12 weeks. Clinical efficacy, tolerability and safety were monitored. Results  Between-group comparisons for efficacy and tolerability revealed no statistically significant differences except for scaling on the trunk at baseline which was significantly worse in the Liarozole group (P = 0.024) and showed a more pronounced improvement in this group than in the acitretin-treated patients (P = 0.047). Based on the overall evaluation of the response to treatment at endpoint, 10 of 15 patients in the Liarozole group and 13 of 16 patients in the acitretin group were considered by the investigator to be at least markedly improved. The expected retinoic acid-related adverse events were mostly mild to moderate and tended to occur less frequently in the Liarozole group. No serious adverse events related to the drugs occurred. Conclusions  The present study indicates that Liarozole at a daily dose of 150 mg is equally effective as a treatment for ichthyosis as acitretin but shows a trend towards a more favourable tolerability profile. The results of this trial warrant further clinical trials to confirm efficacy and safety of Liarozole as an orphan drug in ichthyosis.

  • oral treatment of ichthyosis by the cytochrome p 450 inhibitor Liarozole
    British Journal of Dermatology, 1997
    Co-Authors: G P H Lucker, P.c.m. Van De Kerkhof, P J Boegheim, A M C Heremans, P M Steijlen
    Abstract:

    Liarozole, a novel imidazole derivative, inhibits the cytochrome P450-dependent 4-hydroxylation of retinoic acid, resulting in increased tissue levels of retinoic acid. Twelve male patients with ichthyosis were given oral Liarozole, 150 mg twice daily, in an open study for 12 weeks. Immunohistochemical parameters of inflammation, epidermal proliferation and differentiation were assessed before and after treatment. Extent and severity of the skin lesions was markedly reduced in all patients. Clinical side-effects were reminiscent of those with synthetic retinoids. No relevant changes were found in the haematological, urinary and biochemical parameters. Immunohistochemical assessment showed a statistically significant induction of keratin 4 after Liarozole treatment in 10 of 12 patients. In two of these patients keratin 13 was induced. This open study showed that oral Liarozole treatment was efficacious and well tolerated in the treatment of different types of ichthyosis. The immunohistochemical results suggest a retinoid mechanism as the mode of action.

J Bruynseels - One of the best experts on this subject based on the ideXlab platform.

  • Liarozole fumarate r85246 a novel imidazole in the treatment of receptor positive postmenopausal metastatic breast cancer
    Breast Cancer Research and Treatment, 2000
    Co-Authors: Paul E. Goss, J Bruynseels, Roland De Coster, Amit M Oza, Rakesh Goel, Jeanmarc Nabholtz, Caroline Reid, Nancy Wadden, Michael Crump, L M Tye
    Abstract:

    This phase II study of Liarozole fumarate (R85246, Liarozole), a novel imidazole with retinomimetic and aromatase inhibitory effects, was designed to determine the efficacy and tolerability in postmenopausal women with advanced breast cancer in progression, to correlate these effects with hormonal levels, and to evaluate quality of life. Twenty-nine women with ER-positive or unknown metastatic disease who received ≥ 2 prior hormonal therapies were treated with 150–300 mg Liarozole twice daily until disease progression. All patients were evaluable for toxicity and 25 for response. Four patients (16.0%, 95% CI 5.3–37.4%) had partial remission (PR) of their disease for a median of 7.4 months (range 1.2–12.9) and 7 (28%) had disease stabilization for a median of 4.8 months (1.6–16.0). Estradiol decreased from pre-treatment levels of 9.2–52 pM (mean 17.1) to below detection (9.2 pM, p=0.0005) after 1 month. Similarly estrone levels fell from 14–307 pM (mean 92.7) to below detection (9.2 pM, p=0.0001). The most common toxicity was dermatological (96.6%) with features compatible with hypervitaminosis A syndrome such as rash, pruritus, dry skin, and brittle nails. The majority of these were mild to moderate in severity. No significant improvement in quality of life scores (FLI-C) were noted. Liarozole is an active new treatment for breast cancer in patients heavily pre-treated with hormone therapies. Further studies are needed to confirm its relative efficacy in both receptor positive and negative postmenopausal breast cancer.

  • early clinical experience with Liarozole liazal in patients with progressive prostate cancer
    European Journal of Cancer, 1998
    Co-Authors: Louis Denis, F M J Debruyne, P De Porre, J Bruynseels
    Abstract:

    Abstract Liarozole (Liazal™) is the first retinoic acid (RA) metabolism blocking agent (RAMBA) in clinical practice. RAMBA therapy promotes differentiation and inhibits proliferation by increasing endogenous RA in tumours. Liarozole was investigated in two open-label pilot studies of 100 patients with progressive prostate cancer in relapse despite previous androgen ablation. Liarozole (150–300 mg twice daily, for ≥1 month) produced ≥50% reduction in prostate specific antigen (PSA) serum levels in 15 of 30 evaluable patients in study 1 (50%) and 10 of 55 patients in study 2 (18%). PSA responders had more marked reductions in prostatic acid phosphatase, alkaline phosphatase and symptom scores for bone pain and urological symptoms, and improved general well being. Plasma levels of adrenal androgens did not alter during chronic treatment with Liarozole nor at adrenocorticotrophic hormone (ACTH) stimulation test. Liarozole did not alter plasma levels of adrenal androgens or cortisol. Cortisol response to ACTH stimulation was slightly blunted. Liarozole was generally well tolerated. Dermatological adverse events were probably related to increased intracellular RA. Liarozole appears to be a promising treatment option in prostate cancer.

  • original paper early clinical experience with Liarozole liazal 2 in patients with progressive prostate cancer
    1998
    Co-Authors: Louis Denis, F M J Debruyne, P De Porre, J Bruynseels
    Abstract:

    Liarozole (Liazal 2 ) is the first retinoic acid (RA) metabolism blocking agent (RAMBA) in clinical practice. RAMBA therapy promotes diVerentiation and inhibits proliferation by increasing endogenous RA in tumours. Liarozole was investigated in two open-label pilot studies of 100 patients with progressive prostate cancer in relapse despite previous androgen ablation. Liarozole (150‐300 mg twice daily, for 1 month) produced 50% reduction in prostate specific antigen (PSA) serum levels in 15 of 30 evaluable patients in study 1 (50%) and 10 of 55 patients in study 2 (18%). PSA responders had more marked reductions in prostatic acid phosphatase, alkaline phosphatase and symptom scores for bone pain and urological symptoms, and improved general well being. Plasma levels of adrenal androgens did not alter during chronic treatment with Liarozole nor at adrenocorticotrophic hormone (ACTH) stimulation test. Liarozole did not alter plasma levels of adrenal androgens or cortisol. Cortisol response to ACTH stimulation was slightly blunted. Liarozole was generally well tolerated. Dermatological adverse events were probably related to increased intracellular RA. Liarozole appears to be a promising treatment option in prostate cancer. # 1998 Elsevier Science Ltd. All rights reserved.

  • Liarozole r75251 in hormone resistant prostate cancer patients
    The Prostate, 1997
    Co-Authors: G A Dijkman, Louis Denis, P De Porre, J Bruynseels, Fernandez P Del Moral, F M J Debruyne
    Abstract:

    BACKGROUND Liarozole is an imidazole derivative that has been identified as an inhibitor of the cytochrome P450-dependent all-trans retinoid acid (RA) breakdown. RA is one of the principal endogenous compounds that controls growth and differentiation of epithelial tissues in mammals. METHODS Fifty-five patients with hormone-resistant prostate cancer in progression, following at least first-line androgen ablation therapy, were evaluated. Thirty-one patients were treated with Liarozole 300 mg b.i.d., while 24 patients started with 150 mg b.i.d., which was increased to 300 mg b.i.d. after 4 or 8 weeks. Two patients were not evaluable because they withdrew after initial consent. The WHO performance status was 0 (n = 18), 1 (n = 22), 2 (n = 17), and 3 (n = 6). Most patients (80%) used analgesics. RESULTS For 11 out of the 53 patients, treatment lasted less than 1 month (they were therefore not evaluable for response) due to: poor compliance (n = 1); early death (n = 3); side-effects (n = 2); and decline of physical condition and continuous progression (n = 4). One patient refused to report for follow-up. In all responders, except one, the dose was increased to 300 mg b.i.d. In 23 of the 42 patients evaluable for response, the pain score improved. In 5 patients the pain score had reduced from 2 or 3 to 0. In 11 out of the 42 patients there was a 1-point improvement of WHO performance status. The prostatic-specific antigen (PSA) response rate was 41%; 15 out of 42 evaluable patients presented a decrease of > or = 50%, whereas PSA normalized in 2 further patients. Most of the side effects mimicked retinoid acid toxicity: cutaneous manifestations (such as dry skin, dry lips, sticky skin, brittle nails, erythema, or itch). All patients experienced one or more of these side effects. Other side effects include nausea, fatigue, and slight alopecia. CONCLUSIONS Liarozole can be an enrichment of the therapeutic armamentarium for treatment of hormone-resistant prostate cancer patients after first-line androgen ablation therapy without serious toxicity.

  • effect of six retinoids and retinoic acid catabolic inhibitor Liarozole on two glioblastoma cell lines and in vivo experience in malignant brain tumor patients
    1994
    Co-Authors: J Bruynseels, M E Westarp, W Bollag, Hans Konrad Biesalski, N Grossmann, H H Kornhuber
    Abstract:

    Most adult brain malignancies, notably glioblastoma, astrocytoma and spongioblastoma, are of neuro-epithelial origin. Malignant glioma derive from glial cells that regularly express nuclear retinoic acid receptors of the beta type (RAR-β). Via these response elements, retinol derivatives seem to control target cell differentiation. In addition, sufficient retinol or retinoic acid concentrations are necessary for T-helper cell function [1], and cell mediated immunity in general [2, 3] and in brain tumor patients in particular [4]. Free retinol in-vivo circulates at more than a 100 times lower concentrations than RBP-bound retinol [5]. Unlike Vitamin-D and Vitamin-D binding protein, retinol carrier RBP is physiologically regulated by its ligand [6]. RBP binding sites have been demonstrated on choroidal epithelium, suggestive of a retinol transport across the blood brain barrier [7]. Intracellulary, retinol is irreversibly converted to retinoic acid [8], for which more than 20 nuclear receptors have been characterized [9]. Retinoic acid potently induces differentiation in human astrocytoma [10], neuroblastoma [11] and glioblastoma [12, 13]; in glioma cells, both the all-trans and the 13-cis stereoisomer upregulate cell adhesion [14].