isotretinoin and Prostatic-Neoplasms

To test the hypothesis that modulation of Bcl-2 with 13-cis retinoic acid (CRA)/interferon-alpha2b (IFN) with paclitaxel (TAX), or mitoxantrone, estramustine and vinorelbine (MEV) will have clinical activity in men with metastatic castrate-resistant prostate cancer (CRPC).. 70 patients were treated with either MEV (Arm A) in a 3-week cycle or CRA/IFN/TAX with an 8-week cycle (Arm B). Patients were assessed for response, toxicity, quality of life (QOL), and the effect of treatment on Bcl-2 levels in peripheral blood mononuclear cells (PBMC).. The PSA response rates were 50% and 23%, measurable disease response rates (CR+PR) 14% and 15%, and median overall survival 19.4 months and 13.9 months on Arm A and Arm B respectively. Transient grade 4 neutropenia occurred in 18 and 2 patients, and grade 3 to 4 thrombosis in 7 patients and 1 patient in Arm A and Arm B respectively. Patients on Arm B reported a clinically significant decline in QOL between baseline and week 9/10 (.71 s.d.), and a significantly lower level of QOL than Arm A (p = 0.01). As hypothesized, Bcl-2 levels decreased with CRA/IFN therapy only in Arm B (p = 0.03).. Treatment with MEV was well tolerated and demonstrated clinical activity in patients with CRPC. Given the adverse effect of CRA/IFN/TAX on QOL, the study of other novel agents that target Bcl-2 family proteins is warranted. The feasibility of measuring Bcl-2 protein in a cooperative group setting is hypothesis generating and supports further study as a marker for Bcl-2 targeted therapy.. CDR0000067865.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Estramustine; Humans; Interferons; Isotretinoin; Male; Middle Aged; Mitoxantrone; Neoplasm Metastasis; Paclitaxel; Prostatic Neoplasms; Proto-Oncogene Proteins c-bcl-2; Quality of Life; Survival Rate; Teratogens; Treatment Outcome; Vinblastine; Vinorelbine

Based on prior studies demonstrating the effect of 13- cis-retinoic acid and interferon alpha (CRA/IFN) in decreasing the expression of the antiapoptotic protein bcl-2, our prior clinical study of CRA/IFN with paclitaxel (TAX) administered every 3 weeks, and data demonstrating increased activity of weekly TAX against prostate cancer, we designed a phase I study of weekly TAX in combination with CRA/IFN in patients with prostate cancer and other advanced malignancies. To develop a marker of drug effect, we assessed bcl-2 downregulation in patient peripheral blood mononuclear cells (PBMC).. Enrolled in the study were 14 patients with prostate cancer or other advanced malignancies, and 13 were treated with 1 mg/kg CRA on days 1 and 2, 6 MU/m(2) IFN subcutaneously on days 1 and 2, and TAX at increasing doses on day 2 each week for 6 weeks out of an 8-week cycle. The effect of CRA/IFN on bcl-2 expression was assessed in PBMCs by immunoblotting.. The combination of CRA/IFN and TAX was well tolerated. Dose-limiting toxicities (DLT) in the first cycle of therapy included one patient with fever and neutropenia, and one patient with grade 4 hypertriglyceridemia. The recommended phase II dose of TAX in this combination was 80 mg/m(2). Of 13 patients assessable by tumor markers or scans, 5 had stable disease and 2 had a biochemical partial response including a patient with a decrease in PSA of >50% while on study. The assessment of patient PBMC bcl-2 was feasible in ten patients.. This is the first study in which the safety and clinical activity of weekly TAX combined with CRA/IFN has been demonstrated. The assessment of PBMC bcl-2 is feasible in this weekly chemotherapy schedule

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Dose-Response Relationship, Drug; Down-Regulation; Female; Humans; Interferon-alpha; Isotretinoin; Leukocytes, Mononuclear; Male; Middle Aged; Neoplasms; Paclitaxel; Prostatic Neoplasms; Proto-Oncogene Proteins c-bcl-2; Treatment Outcome

13 cis Retinoic acid (isotretinoin) is a retinoid with preclinical evidence of anti-prostate cancer activity. This phase II, cross-over, randomized study of advanced, predominantly androgen-dependent prostate cancer patients was designed to assess primarily the effect on prostate-specific antigen (PSA) decline and toxicity of adding isotretinoin to hormonal therapy and, secondarily, the potential antitumor activity of the combination.. Thirty-seven D0 to D2 patients were randomized soon after initiating luteinizing hormone-releasing hormone agonist with antiandrogen treatment to add (arm 1) or not (arm 2) isotretinoin from weeks 1 to 12. After cross-over on week 13, patients in arm 1 discontinued while patients in arm 2 added isotretinoin from weeks 14 to 25. Observation on hormonal therapy alone continued until week 49.. Baseline and randomization median PSA for 30 assessable patients were, respectively, 34 and 18.2 ng/mL for arm 1 and 31 and 13.4 ng/mL for arm 2. Median PSA at week 13 was 0.5 ng/mL (range, < 0.05 to 136 ng/mL) for arm 1 and 0.7 ng/mL (range, < 0.05 to 4.4 ng/mL) for arm 2; at week 25, 0.1 ng/mL (range, < 0.05 to 121 ng/mL) and 0.4 ng/mL (range, < 0.05 to 3.1 ng/mL), respectively. At week 49, arm 1 had median PSA of 0.1 ng/mL (range, < 0.05 to 345 ng/mL) and arm 2, 0.3 ng/mL (range, < 0.05 to 8.8 ng/mL); seven of 15 and three of 15 patients, respectively, had undetectable PSA levels (P =.12). Frequent isotretinoin-related toxicity included grade 1 cheilitis (76%), skin dryness (43%), and elevated triglycerides (50%).. Isotretinoin does not impair PSA decline or add significant toxicity to hormonal therapy. An adequately powered, randomized study would be required to determine whether the combination is superior to standard hormonal treatment.

Topics: Administration, Oral; Aged; Androgen Antagonists; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Combined Modality Therapy; Cross-Over Studies; Humans; Injections, Subcutaneous; Isotretinoin; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Skin Diseases; Treatment Outcome; Triglycerides

Recent studies demonstrate that retinoids decrease expression of the anti-apoptotic protein bcl-2, enhance the effect of chemotherapy, and act synergistically with interferon alfa (IFNalpha) to inhibit tumor cell growth in vitro. A phase I trial of 13-cis-retinoic acid (CRA), IFNalpha, and paclitaxel (TAX) was conducted to determine the toxicity and recommended phase II dose of this combination. Pharmacodynamic studies were performed to determine whether CRA and IFNalpha could modulate bcl-2 expression in vitro and in patients.. Twenty-two patients with prostate cancer or other advanced malignancies were treated with CRA/IFNalpha and escalating doses of TAX. The effect of CRA/IFNalpha on TAX pharmacokinetics was analyzed in both patients and human liver microsomes. The effect of CRA/IFNalpha on bcl-2 expression was assessed in vitro and in peripheral-blood mononuclear cells (PBMCs) by immunoblotting.. CRA 1 mg/kg on days 1 to 4, IFNalpha 6 MU/m(2) subcutaneously on days 1 to 4, and TAX 175 mg/m(2) on day 3 was well tolerated. Pharmacokinetic studies demonstrated that CRA/IFNalpha caused a 33% decrease in TAX clearance and a 23% decrease in the area under the concentration-time curve values of the TAX metabolite 6-alfa-hydroxytaxol (6-HT). CRA alone reduced conversion of TAX to 6-HT by 41% in human liver microsomes. CRA/IFNalpha decreased bcl-2 expression in vitro and in PBMCs.. CRA/IFNalpha and TAX is a well-tolerated regimen. CRA/IFNalpha increases TAX area under the concentration-time curve through an inhibitory effect of CRA on the metabolism of TAX to 6-HT. CRA/IFNalpha can modulate bcl-2 expression in vitro and demonstrates similar biologic activity in patients. Further studies will determine the activity of CRA/IFNalpha/TAX and validate the assessment of bcl-2 in PBMCs as a marker of tumor response.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Dose-Response Relationship, Drug; Female; Humans; In Vitro Techniques; Interferon-alpha; Isotretinoin; Leukocytes, Mononuclear; Liver; Male; Microsomes; Middle Aged; Paclitaxel; Prostatic Neoplasms; Proto-Oncogene Proteins c-bcl-2; Tumor Cells, Cultured

The objective of this study was to test the hypothesis that 13-cis-retinoic acid (CRA) and alpha-interferon (IFN-alpha) have antitumor activity in patients with early recurrence of prostate cancer measured by rising prostate-specific antigen (PSA) after local therapy, and that this activity is associated with the increase of plasma transforming growth factor beta1 (TGF-beta1). Thirty patients with a PSA > 7 ng/ml that increased >0.4 ng/ml/month after initial radiation therapy or a PSA > 2.0 ng/ml after prostatectomy were treated with 1 mg/kg/day of CRA and 3 million units of IFN-alpha administered three times per week. Patients were followed clinically with serum measurements of PSA and assessment of toxicity. Biological activity of CRA and IFN-alpha was assessed by the measurement of plasma TGF-beta1. Twenty-six percent of patients had a partial (50% decrease maintained for 1 month) or minimal (<50% decrease maintained for 1 month) biochemical response of PSA, with a median decrease of 23% (11-55%) at 3 months. Plasma TGF-beta1 levels increased with CRA and IFN-alpha therapy and correlated with a decrease in PSA; patients with a decrease in PSA had a 151% increase in TGF-beta1 compared to 27% in patients without a decrease in PSA (P = 0.04). CRA and IFN-alpha can produce transient reduction or stabilization of PSA. The measurement of plasma TGF-beta1 at 1 month of therapy correlates with changes in PSA and may represent a useful marker for the biological effect of these agents; further analysis in larger numbers of patients and methods to optimize these effects should be explored.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Biomarkers, Tumor; Follow-Up Studies; Humans; Interferon alpha-2; Interferon-alpha; Isotretinoin; Male; Middle Aged; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Recombinant Proteins; Transforming Growth Factor beta

Combination of two differentiation agents such as phenylbutyrate (PB) and 13-cis-retinoic acid (CRA) has been shown to have an additive inhibitory effect on tumor growth in preclinical studies. In this report we explored the hypotheses that these "cytostatic" agents may have a greater antitumor activity in combination with "cytotoxic" compounds and their biological effect may be sequence-dependent.. The antitumor activity of combination of PB and CRA with paclitaxel (TX ) and doxorubicin (DOXO) on human prostate and colon carcinoma cell lines was assessed both in vitro and in vivo. The effect on cell cycle, apoptotic rate, cyclin expression and induction of p21 expression was also determined.. Following treatment of tumor cells with PB + CRA + TX or DOXO, inhibition of tumor cell growth was greatly enhanced as compared to PB + CRA, TX or DOXO alone, with >90% growth inhibition. However, when the cells were pretreated with PB + CRA followed by TX or DOXO, the enhanced inhibition was abolished suggesting a protective effect to this sequence. Interestingly treatment with PB + CRA restored sensitivity to DOXO in PC-3 human prostate cancer cell line. PB + CRA induced p21 expression and cell-cycle arrest in G1 phase, while TX and DOXO induced G2/M arrest. p21 and p53-deficient colon carcinoma cell lines were more sensitive to the effect of PB + CRA and TX as single agents and in combination, as compared to the wild type cells. When p21-deficient cells were pretreated with PB + CRA followed by TX the protective effect was still observed. Treatment of tumor cells with combination of these drugs induced cell cycle delay at multiple mitotic checkpoints before undergoing apoptosis. Tumor growth was significantly inhibited and delayed in animals treated with either TX or concomitantly with TX and PB + CRA as compared to control. Animals treated with all three agents demonstrated further growth inhibition or delay than the TX alone or PB + CRA arm.. These results suggest a rational therapeutic approach for combination of differentiation-inducing agents with cytotoxic drugs given concomitantly, but not sequentially.

Topics: Antineoplastic Agents; Apoptosis; Carcinoma; Cell Cycle; Cell Differentiation; Cell Division; Cell Line, Tumor; Colonic Neoplasms; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; Flow Cytometry; Humans; Isotretinoin; Male; Phenylbutyrates; Polymerase Chain Reaction; Prostatic Neoplasms

Physicians make some medical decisions without disclosure to their patients. Nondisclosure is possible because these are silent decisions to refrain from screening, diagnostic or therapeutic interventions. Nondisclosure is ethically permissible when the usual presumption that the patient should be involved in decisions is defeated by considerations of clinical utility or patient emotional and physical well-being. Some silent decisions--not all--are ethically justified by this standard. Justified silent decisions are typically dependent on the physician's professional judgment, experience and knowledge, and are not likely to be changed by patient preferences. We condemn the inappropriate exclusion of the patient from the decision-making process. However, if a test or treatment is unlikely to yield a net benefit, disclosure and discussion are at times unnecessary. Appropriate silent decisions are ethically justified by such considerations as patient benefit or economy of time.

Topics: Acne Vulgaris; Adult; Alzheimer Disease; Contraception Behavior; Cost-Benefit Analysis; Decision Making; Ethics, Clinical; Ethics, Medical; Female; Headache; Humans; Isotretinoin; Male; Mass Screening; Patient Participation; Personal Autonomy; Prostatic Neoplasms; Teratogens; Truth Disclosure

In retinoid resistant epithelial tumors, the lack of retinoic acid receptor beta2 (RARbeta2) expression due to epigenetic silencing impairs the activation of retinoid target genes including RARbeta2, and has been associated with the development of cancer. In this study we developed a strategy to monitor the re-activation of RARbeta2 by chromatin remodeling agents combined with retinoids in real time, and to correlate the RARbeta2 re-activation with anti-tumor activity.. We selected the RARbeta2-negative retinoid resistant human prostate carcinoma cell line PC3 and stably transfected it with a luciferase expression vector under the control of a functional segment of RARbeta2 promoter (pGL2-RARbeta2-PC3). Then, we used the bioluminescence technology to monitor the reporter gene expression in real time both in vitro and in vivo following combination treatment with the histone deacetylase inhibitor MS-275 and 13-cis retinoic acid (CRA). Based on the effective dose for the RARbeta2 re-activation, we tested the anti-tumor activity of this drug combination.. Following combination treatment with MS-275 and CRA, we observed endogenous RARbeta2 re-expression, acetylation at the RARbeta2 promoter level, and synergistic activation of the luciferase reporter gene by real time imaging both in vitro and in vivo. Combination treatment with MS-275 and CRA restored retinoid sensitivity in human prostate carcinoma cell lines, and had a greater inhibitory effect on tumor cell growth than single agents in vitro and in vivo.. This study provides evidence that HDAC inhibitors restore retinoid sensitivity in prostate cancer cells, and in vivo real time imaging of RARbeta2 activation may represent a useful tool to study the pharmacodynamics of combination therapy with HDAC inhibitors and retinoids.

Topics: Animals; Benzamides; Cell Line, Tumor; Drug Therapy, Combination; Enzyme Inhibitors; Epigenesis, Genetic; Genes, Reporter; Histone Deacetylase Inhibitors; Humans; Isotretinoin; Luciferases; Male; Mice; Mice, Nude; Promoter Regions, Genetic; Prostatic Neoplasms; Pyridines; Receptors, Retinoic Acid; Transcriptional Activation; Xenograft Model Antitumor Assays

We have investigated new drug combinations of potential clinical value for treatment of hormone-refractory prostate cancer. Combinations of paclitaxel, carboplatin and mitoxantrone, and combinations of these three drugs with compounds targeting important pathways for cancer progression, 13-cis-retinoic acid and chelerythrine, were assessed. The drugs combinations were incubated for 72 h in steroid-free conditions with two androgen-independent cell lines, DU145 and PC3. Cytotoxicity assay was performed using resazurin and Hoescht 33342. Synergism and antagonism were measured by the combination index, and calculated for each combination by the median-effect method. All six compounds exhibited cytotoxic effects when tested alone. Paclitaxel exhibited the highest and 13-cis-retinoic acid the lowest effect on both cell lines. Paclitaxel demonstrated synergism or additivity with 13-cis-retinoic acid in both cell lines, whereas antagonistic effects were observed when it was tested in combination with carboplatin. Chelerythrine showed additive effects with mitoxantrone in both cell lines and with paclitaxel in PC3 cells. Our results suggest that combination of paclitaxel and 13-cis-retinoic acid, and of chelerythrine with mitoxantrone and paclitaxel, may have clinical value for the treatment of hormone-refractory prostate cancer.

Topics: Alkaloids; Antineoplastic Combined Chemotherapy Protocols; Benzophenanthridines; Carboplatin; Drug Antagonism; Drug Synergism; Humans; In Vitro Techniques; Isotretinoin; Male; Mitoxantrone; Neoplasms, Hormone-Dependent; Paclitaxel; Phenanthridines; Prostatic Neoplasms; Treatment Outcome; Tumor Cells, Cultured

The need for statistical methodologies for analysing a small size study, such as a pilot or so-called 'proof of concept' study, has not been paid much attention in the past. Recently the Institute of Medicine (IOM) formed a committee and held a workshop to discuss methodologies for conducting clinical trials with small number participants. In this paper we argue that the hypothesis of treatment effect in a small pilot study should be set up to test whether any individual subject has an effect rather than whether the group mean or median has shifted as often done for large, confirmatory clinical trials. Based on this paradigm we propose multiple test procedures as one option when individuals have enough observations, and a mixture-distribution approach when individuals have one or more observations. The latter approach may be used in either a one- or two-group setting, and is our focus in this paper. We present the likelihood ratio tests for the mixture models. Examples are given to demonstrate the methods.

Topics: Clinical Trials, Phase I as Topic; Computer Simulation; Data Interpretation, Statistical; Drug Therapy, Combination; Humans; Interferon-alpha; Isotretinoin; Likelihood Functions; Male; Persian Gulf Syndrome; Pilot Projects; Prostate-Specific Antigen; Prostatic Neoplasms; Transforming Growth Factor beta; Vehicle Emissions

Differentiation-inducing agents, such as retinoids and short-chain fatty acids, have an inhibitory effect on tumor cell proliferation and tumor growth in preclinical studies. Clinical trials involving these compounds as single agents have been suboptimal in terms of clinical benefit. Our study evaluated the combination of phenylbutyrate (PB) and 13-cis retinoic acid (CRA) as a differentiation and antiangiogenesis strategy for prostate cancer. On the basis of previous evidence, common signal transduction pathways and possible modulation of retinoid receptors and retinoid response elements by PB could be responsible for such activities. We assessed the effect of the combination of PB and CRA on human and rodent prostate carcinoma cell lines. The combination of PB and CRA inhibited cell proliferation and increased apoptosis in vitro in an additive fashion as compared with single agents (P < 0.014). Prostate tumor cells treated with both PB and CRA revealed an increased expression of a subtype of retinoic acid receptor (retinoic acid receptor-beta), suggesting a molecular mechanism for the biological additive effect. The combination of PB and CRA also inhibited prostate tumor growth in vivo (up to 82-92%) as compared with single agents (P < 0.025). Histological examination of tumor xenografts revealed decreased in vivo tumor cell proliferation, an increased apoptosis rate, and a reduced microvessel density in the animals treated with combined drugs, suggesting an antiangiogenesis effect of this combination. Thus, endothelial cell treatment with both PB and CRA resulted in reduced in vitro cell proliferation. In vivo testing using the Matrigel angiogenesis assay showed an additive inhibitory effect in the animals treated with a combination of PB + CRA (P < 0.004 versus single agents). In summary, this study showed an additive inhibitory effect of combination of differentiation agents PB and CRA on prostate tumor growth through a direct effect on both tumor and endothelial cells.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Cycle; Cell Differentiation; Cell Division; Drug Synergism; Endothelium, Vascular; Growth Inhibitors; Humans; Isotretinoin; Male; Mice; Mice, Inbred C57BL; Mice, Nude; Neovascularization, Pathologic; Phenylbutyrates; Prostatic Neoplasms; Receptors, Retinoic Acid; Tumor Cells, Cultured

The objective of this study was to determine whether there is any beneficial effect of oral 13-cis-retinoic acid (isotretinoin) on prostate cancer, using serum prostate-specific antigen (PSA) levels as a surrogate end point in patients with a rising serum PSA after radical prostatectomy. In the first phase, the effect of the drug on the serum PSA level was tested in 14 control patients with normal prostates. Our goal was to exclude any effect of isotretinoin on PSA secretion and metabolism and thus to validate any observed effect on PSA as indicative of anticancer activity. In the second phase, patients with rising PSA levels after radical prostatectomy and no evidence of metastatic disease were treated with oral isotretinoin at a daily dose of 1.0 mg/kg. Serum PSA levels were checked monthly for the first 4 months after initiation of treatment and every 3 months thereafter. No significant changes in serum PSA levels after 3 months of isotretinoin treatment were recorded in the control group (P = 1.000). Three of 11 postprostatectomy patients (27%) had a PSA reduction of 28%, 15%, and 6.6% after initiation of treatment that lasted for a period of 2-3 months. In two of these three patients, the PSA levels subsequently rose exponentially. Another patient displayed a stabilization of the serum PSA curve for 3 months after an initial sharp rise. No grade 3 or 4 toxicity was recorded in this group of patients. Isotretinoin had a modest, transient effect on the serum PSA level in 4 of 11 (36%) patients with a rising serum PSA after radical prostatectomy. We conclude that this drug is unlikely to be of major therapeutic benefit in prostate cancer patients when used as a single agent. However, its modest effect argues for the exploration of other, more potent retinoids for prostate cancer therapy.

Topics: Adult; Aged; Aged, 80 and over; Humans; Isotretinoin; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Time Factors

The present study was designed to investigate the effects of 13-cis-retinoic acid (13-cis-RA) (100 micrograms/mouse/day) and androgen ablation (castration) alone and in combination on growth of a human prostatic carcinoma line (LNCaP) transplanted to athymic nude mice as an experimental model. The results of these studies suggest that; (1) androgen ablation (castration) significantly decreased the size of LNCaP xenograft as compared to untreated animals; (2) when 13-cis-RA was administered to nude mice carrying established tumors (0.51 +/- 0.04 cm3), the tumor size was significantly reduced as compared to untreated controls (0.65 +/- 0.06 cm3 versus 1.63 +/- 0.12 cm3). About 50% of the animals in this group showed xenografts necrosis followed by complete regression of tumors by five months; (3) the combination of androgen ablation and 13-cis-RA treatment to nude mice carrying tumors showed synergistic effect in decreasing the tumor size. These results indicate that combination therapies based on androgen ablation and retinoid administration may be a useful approach for the treatment of prostate cancer.

Topics: Animals; Humans; Isotretinoin; Male; Mice; Mice, Nude; Necrosis; Neoplasm Transplantation; Orchiectomy; Prostatic Neoplasms; Tumor Cells, Cultured

Prostate-specific antigen (PSA) is a member of the kallikrein family and has been an important biological marker for prostate cancer. The mechanisms regulating PSA expression in prostatic cancer cells are unclear. The present study was designed to elucidate the role of 13-cis-retinoic acid (RA) in regulation of PSA and the tumorigenic potential of the human prostate cancer cell line LNCaP. The growth regulation of LNCaP cells was examined by DNA synthesis and doubling time. The tumorigenic potential of prostate cancer cells was analyzed by soft agar colony-forming assay, in vitro invasion assay, type IV collagenase assay and binding to extracellular matrix assay. The nuclear receptors for retinoic acid (RAR alpha, -beta, -gamma and RXR alpha, -beta, -gamma) as well as PSA mRNA were determined by Northern blot using specific oligonucleotide probes. Our results suggest that 13-cis-RA significantly inhibits PSA secretion and expression both at the mRNA and protein levels compared with untreated cells. Electron microscopic studies suggest that after 13-cis-RA treatment, cells become more differentiated as they contain lumina, lined by plasma membrane and microvilli. Prostate cancer cell growth and tumorigenic potential after 13-cis-RA treatment was significantly decreased compared with controls. Nude mice tumorigenicity studies showed that 13-cis-RA-treated cells produced significantly smaller tumors compared with untreated cell tumors. There was also a significant increase in the expression of RXRa mRNA after 13-cis-RA treatment compared with untreated cells.

Topics: Animals; Cell Division; Collagen; DNA, Neoplasm; Fibronectins; Gene Expression; Humans; Isotretinoin; Laminin; Male; Mice; Mice, Nude; Microscopy, Electron; Neoplasm Invasiveness; Neoplasm Transplantation; Prostate-Specific Antigen; Prostatic Neoplasms; Receptors, Retinoic Acid; RNA, Messenger; Tumor Cells, Cultured

The purpose of this study was to examine the effects of 13-cis-retinoic acid (13-cis-RA) on the growth regulation of DU-145 human prostatic cancer cells. The results of these experiments demonstrate that cell growth and metastatic potential of DU-145 cells were significantly inhibited by 13-cis-RA (10 microM). In order to elucidate the possible molecular mechanisms of 13-cis-RA action on prostate cancer cells, we examined the expression of nuclear receptor genes (hRXR alpha) and found that 13-cis-RA treated cells showed higher mRNA expression for hRXR alpha nuclear receptors compared to untreated cells. To elucidate further the possible biochemical mechanisms associated with these alterations, we analyzed the phosphorous metabolites by MR spectroscopy and found that the major metabolites were PME, (PC, PE) and DPDE (UDP-GalNAc, UDP-GLcNAc). The DU-145 cells and xenografts, which were both treated with 13-cis-RA, showed a two-fold decrease in DPDE's, compared to their controls. The higher resolution spectra of perfused cells revealed that phosphocholine levels were twice as high in 13-cis-RA-treated DU-145 cells as compared to untreated cells. These investigations demonstrate for the first time that 13-cis-RA inhibits the growth of human prostatic cancer cells, and this inhibition is associated with an increase in hRXR alpha nuclear receptor gene expression and alterations in phosphorous metabolites detected by 31P MR spectroscopy.

Topics: Animals; Cell Division; Collagen; Collagenases; Fibronectins; Gene Expression; Humans; Isotretinoin; Laminin; Magnetic Resonance Spectroscopy; Male; Matrix Metalloproteinase 9; Mice; Mice, Nude; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Transplantation; Prostatic Neoplasms; Receptors, Retinoic Acid; Tumor Cells, Cultured

Liarozole fumarate (R85,246), a novel benzimidazole derivative, reduced s.c. and bone metastasis tumor growth by the androgen-independent PC-3ML-B2 human prostatic carcinoma clone in SCID mice. The drug inhibited cell invasion of Matrigel in Boyden chamber chemotactic assays and the secretion of type IV collagenase. In vitro, liarozole failed to inhibit cell proliferation and cell attachment to various substrates (Matrigel, laminin, type IV collagen, and fibronectin). In vivo, the drug also blocked type IV collagenase production in established s.c. tumors. Liarozole has been postulated by others (R. De Coster, W. Wouters, R. Van Ginckel, D. End, et al. J. Steroid Biochem. Mol. Biol., 43: 197-201, 1992) to inhibit retinoic acid catabolism. Our data indicate that liarozole treatment can increase the tumor retinoic acid levels in vivo. Studies of retinoic acid revealed that the drug independently reduced tumor growth in vivo and inhibited cell invasion of Matrigel and the secretion of collagenase IV. Surprisingly, liarozole and retinoic acid failed to exhibit measurable synergistic activity both in vitro and in vivo. Taken together these data suggest that liarozole might inhibit retinoic acid catabolism in vivo and consequently have significant therapeutic value as an anti-prostatic tumor agent.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Cell Adhesion; Cell Division; Cell Survival; Chemotactic Factors; Collagenases; Disease Models, Animal; Humans; Imidazoles; Isotretinoin; Male; Matrix Metalloproteinase 9; Mice; Mice, SCID; Neoplasm Invasiveness; Neoplasm Transplantation; Prostatic Neoplasms; Tumor Cells, Cultured

Retinoids play a major role in regulation of epithelial cell growth and cellular differentiation, but their mechanism(s) of action are still unclear. In the present study, we examined the effects of 13-cis-retinoic acid (13-cis-RA) on cytotoxicity, growth properties, morphology, neutral lipids, phospholipids and fatty acids in cultured human prostate cancer cell lines. The results of these experiments suggest that 13-cis-RA (10 microM) inhibits the DNA synthesis and nude mice tumorigenicity by 2- to 3-fold, compared to control. Electron microscopy revealed more differentiated phenotypes after 13-cis-RA treatment. There was a significant increase in phosphatidylcholine and decrease in sphingomyelin in 13-cis-RA treated cells compared to control. The saturated fatty acids significantly decreased whereas unsaturated fatty acids were increased after 13-cis-RA treatment in prostate cancer cells. This study demonstrates for the first time that retinoic acid mediated downregulation of saturated fatty acids and upregulation of unsaturated fatty acid in human prostate cancer cells.

Topics: Animals; Cell Survival; Down-Regulation; Fatty Acids; Fatty Acids, Unsaturated; Humans; Isotretinoin; Male; Mice; Mice, Nude; Microscopy, Electron; Prostatic Neoplasms; Tumor Cells, Cultured; Up-Regulation