fenretinide and Adenocarcinoma

Fenretinide is a synthetic retinoid that is cytotoxic to a variety of cancers. We conducted a phase II trial of oral fenretinide in patients with biochemically recurrent prostate cancer.. Eligible patients had histologically confirmed prostate cancer and a confirmed rising prostate-specific antigen (PSA) >or= 2 ng/mL following either radical prostatectomy and/or pelvic radiation therapy, without clinical or radiographic evidence of metastasis. The primary endpoint was PSA response, which was defined as a confirmed decrease by >or=50%, and >or=5 ng/mL, from the pretreatment value. Treatment comprised oral fenretinide 900 mg/m2 twice daily for 1 week, every 3 weeks, for 1 year.. After a median follow-up of 17.7 months, out of 23 patients, 7 (30%) patients had PSA stable disease (SD), 11 (48%) patients had PSA progression within 3 months, 4 patients had minimal increases over 3 months that did not qualify as SD or progression (17%), and one patient (4%) was not evaluable. Median time to PSA progression was 4.6 months (95% CI, 3.2-8.2 months). Observed grade 3 toxicities included fatigue, pain, hypermagnesemia, a rise in lipase, and nyctalopia.. Although well-tolerated, oral fenretinide did not meet prespecified PSA criteria for response in biochemically recurrent prostate cancer; however, 30% of patients had SD, which suggests modest single-agent clinical activity. The role of different formulations of fenretinide, which might allow for higher serum concentrations of the drug, is currently under investigation.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents; Disease Progression; Fenretinide; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Prostatectomy; Prostatic Neoplasms; Treatment Outcome

An NCI-sponsored, phase II trial of N-(4-hydroxyphenyl)- retinamide (4-HPR) in patients with organ-confined prostate cancer in the period prior to radical prostatectomy was carried out. Thirty-seven men with the histologic diagnosis of prostate cancer planning to have radical prostatectomy entered the study after informed consent and were given 4-HPR (or matching placebo) as a single daily dose (two 100-mg capsules of 4-HPR or two capsules of placebo daily) for 3 weeks prior to surgery. Four men dropped out for unrelated reasons. Thirty-three men completed the study. At the time of surgery, repeat biopsies of the prostate were performed to study the effects of the drug on potential surrogate endpoint biomarkers (SEBs) of malignancy within the tissue. The panel of potential SEBs of malignancy include p53, cytomorphometric indices, ploidy, PNCA, erbB-2, erbB-3, EGF receptor, TGF-alpha tumor-associated glycoprotein-72, fatty acid synthetase and Lewis Y antigen. Twenty-three patients had matching pre- and posttherapy lesions and were considered informative. Results from the patients indicate significant differential expression of biomarkers in pretreatment specimens of uninvolved prostatic tissue (normal-appearing epithelia) prostatic intraepithelial neoplasia (PIN) and prostate cancer. The mean erbB-2 expression was 0.58 in uninvolved vs. 1.04 in PIN (p = 0.002); while the mean erbB-2 expression was 1.35 in prostate cancer (p = 0.0007, uninvolved vs. prostate cancer). A similar pattern of increased biomarker expression between uninvolved and PIN or prostate cancer tissues can be observed for EGF receptor (mean = 1.21, 1.87 and 1.76 for uninvolved, PIN and prostate cancer, respectively) and erbB-3 (mean = 0.81, 1.59 and 1.30 for uninvolved, PIN and prostate cancer, respectively). There were no statistically significant differences in biomarkers observed in the 4-HPR-treated patients when compared with placebo-treated control patients. There was a posttreatment up-regulation of biomarkers observed in both groups of patients. This observation is most likely explained by an effect due to the diagnostic sextant biopsy equally affecting both groups of patients. Results from this study do not demonstrate a chemoprevention effect of 4-HPR on tissue-based SEBs at the dose given.

Topics: Adenocarcinoma; Aged; Antineoplastic Agents; Biomarkers, Tumor; Biopsy, Needle; Fenretinide; Humans; Immunohistochemistry; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Reference Values; Sensitivity and Specificity; Statistics, Nonparametric

Prostate cancer is the most common cancer diagnosed in American men. The need to find effective means of preventing this disease is clear. Vitamin A and its analogues (retinoids) act as transcriptional regulators within the nucleus and have been tested as both preventative and therapeutic agents in human malignancy. Fenretinide (N-4-hydroxyphenyl retinamide) (4HPR) has been found to be relatively nontoxic in preclinical experiments and early clinical trials. Its toxicity and feasibility for use as a chemoprevention agent in men at high risk for prostate cancer was evaluated in this study. Twenty-two patients were entered into a clinical trial that involved taking 4HPR for twelve 28-day cycles. Eight patients with negative prestudy biopsies had positive prostate biopsies prior to or at the time of their 12th cycle evaluation. This led to early closure of the study. 4HPR was well-tolerated, and no major toxicities were associated with its use. The significance of this study is limited due to small sample size. Chemoprevention studies such as this can be difficult to complete because of the commitment required of otherwise healthy individuals; nevertheless additional dosages and schedules for 4HPR administration merit further investigation.

Topics: Adenocarcinoma; Aged; Anticarcinogenic Agents; Biopsy; Feasibility Studies; Fenretinide; Humans; Male; Middle Aged; Prostatic Neoplasms

Considerable attention has been focused on the chemopreventive properties of fenretinide against carcinogen-induced rodent mammary cancer. Less is known about its direct antitumor effects. The combination of tamoxifen and fenretinide is more effective than tamoxifen or fenretinide alone in prevention of rat mammary cancer. However, the combined toxicity of tamoxifen plus fenretinide in humans is unknown. Therefore, we performed a phase I/II trial in women with estrogen receptor (ER)-positive or progesterone receptor (PR)-positive, previously untreated metastatic breast cancer.. Groups of three patients received tamoxifen 20 mg/d, or tamoxifen plus fenretinide 100, 200, 300, or 400 mg/d. Patients who received fenretinide enjoyed a 3-day "drug holiday" every 4 weeks. Serum levels of fenretinide and its major metabolites were monitored. Patients were monitored for known toxicities of tamoxifen and vitamin A analogs, as well as for response.. There were no significant adverse effects on renal, hepatic, hematologic, or lipid values. Nyctalopia, photophobia, cheilitis, and pruritus were not observed. Improvement or stabilization of disease occurred in 12 of 15 patients.. We conclude that tamoxifen administered with fenretinide is nontoxic. Phase III trials of tamoxifen versus tamoxifen plus fenretinide are warranted.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Fenretinide; Humans; Middle Aged; Tamoxifen; Treatment Outcome

Our recent study showed that tetrathiomolybdate (TM), a drug to treat copper overload disorders, can sensitize drug-resistant endometrial cancer cells to reactive oxygen species (ROS)-generating anticancer drug doxorubicin. To expand these findings in the present study we explore TM efficacy in combination with a spectrum of ROS-generating anticancer drugs including mitomycin C, fenretinide, 5-fluorouracil and doxorubicin in ovarian cancer cells as a model system.. The effects of TM alone or in combination with doxorubicin, mitomycin C, fenretinide, or 5-fluorouracil were evaluated using a sulforhodamine B assay. Flow cytometry was used to detect the induction of apoptosis and ROS generation. Immunoblot analysis was carried out to investigate changes in signaling pathways.. TM potentiated doxorubicin-induced cytotoxicity and modulated key regulators of apoptosis (PARP, caspases, JNK and p38 MAPK) in SKOV-3 and A2780 ovarian cancer cell lines. These effects were linked to the increased production of ROS, as shown in SKOV-3 cells. ROS scavenging by ascorbic acid blocked the sensitization of cells by TM. TM also sensitized SKOV-3 to mitomycin C, fenretinide, and 5-fluorouracil. The increased cytotoxicity of these drugs in combination with TM was correlated with the activity of ROS, loss of a pro-survival factor (e.g. XIAP) and the appearance of a pro-apoptotic marker (e.g. PARP cleavage).. Our data show that TM increases the efficacy of various anticancer drugs in ovarian cancer cells in a ROS-dependent manner.

Topics: Adenocarcinoma; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blotting, Western; Cell Death; Cell Line, Tumor; Doxorubicin; Female; Fenretinide; Flow Cytometry; Fluorouracil; Humans; Mitomycin; Molybdenum; Ovarian Neoplasms; Reactive Oxygen Species

The scaffold protein Islet-Brain1/c-Jun amino-terminal kinase Interacting Protein-1 (IB1/JIP-1) is a modulator of the c-Jun N-terminal kinase (JNK) activity, which has been implicated in pleiotrophic cellular functions including cell differentiation, division, and death. In this study, we described the presence of IB1/JIP-1 in epithelium of the rat prostate as well as in the human prostatic LNCaP cells. We investigated the functional role of IB1/JIP-1 in LNCaP cells exposed to the proapoptotic agent N-(4-hydroxyphenyl)retinamide (4-HPR) which induced a reduction of IB1/JIP-1 content and a concomittant increase in JNK activity. Conversely, IB1/JIP-1 overexpression using a viral gene transfer prevented the JNK activation and the 4-HPR-induced apoptosis was blunted. In prostatic adenocarcinoma cells, the neuroendocrine (NE) phenotype acquisition is associated with tumor progression and androgen independence. During NE transdifferentiation of LNCaP cells, IB1/JIP-1 levels were increased. This regulated expression of IB1/JIP-1 is secondary to a loss of the neuronal transcriptional repressor neuron restrictive silencing factor (NRSF/REST) function which is known to repress IB1/JIP-1. Together, these results indicated that IB1/JIP-1 participates to the neuronal phenotype of the human LNCaP cells and is a regulator of JNK signaling pathway.

Topics: Adaptor Proteins, Signal Transducing; Adenocarcinoma; Adenoviridae; Animals; Apoptosis; Benzimidazoles; Blotting, Northern; Blotting, Western; Cell Differentiation; Cell Line, Tumor; Densitometry; Disease Progression; Enzyme Activation; Epithelial Cells; Fenretinide; Gene Expression Regulation, Neoplastic; HeLa Cells; Humans; JNK Mitogen-Activated Protein Kinases; Luciferases; Male; MAP Kinase Kinase 4; Microscopy, Fluorescence; Mitogen-Activated Protein Kinase Kinases; Neoplasms; Neurons; Neurosecretory Systems; Phenotype; Plasmids; Prostate; Prostatic Neoplasms; Rats; Repressor Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA; Synaptophysin; Tetrazolium Salts; Thiazoles; Tissue Distribution; Transcription Factors; Transcription, Genetic; Up-Regulation

Fenretinide [N-(4-Hydroxyphenyl)retinamide, 4-HPR] (10(-10)-10(-6) M) treatment of HT-29 human colon cancer cells for 24-72 h significantly inhibited their growth. Using HCT-15 cells, 4-HPR had limited inhibitory effects on cell proliferation over the same concentration range and time period. The inhibitory effects of 4-HPR on cell growth in HT-29 cells were markedly reduced in the presence of exogenously added prostaglandins (PGs), suggesting a possible role for inhibition of PG synthesis as a mechanism for 4-HPR's antiproliferative effects. Inhibition of PGE(2) production was caused by 4-HPR in a concentration-dependent manner and decreased COX-2 but not COX-1 mRNA levels; this is the first indication that 4-HPR selectively inhibits COX-2 gene expression. Our findings suggest a possible mechanism for the chemopreventive and anti-proliferative effects of 4-HPR.

Topics: Adenocarcinoma; Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Division; Colonic Neoplasms; Cyclooxygenase 1; Cyclooxygenase 2; Dinoprostone; Dose-Response Relationship, Drug; Down-Regulation; Fenretinide; Humans; Isoenzymes; Kinetics; Membrane Proteins; Phorbol Esters; Prostaglandin-Endoperoxide Synthases; Retinoids; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Time Factors; Tumor Cells, Cultured

Retinoids are a class of natural or synthetic compounds that participate in the control of cell proliferation, differentiation and fetal development. The synthetic retinoid fenretinide (HPR) inhibits carcinogenesis in various animal models. Retinoids have also been suggested to be effective inhibitors of angiogenesis. The effects of HPR on certain endothelial cell functions were investigated in vitro, and its effects on angiogenesis was studied in vivo, by using the chorioallantoic membrane (CAM) assay. HPR inhibited vascular endothelial growth factor- (VEGF-) and fibroblast growth factor-2- (FGF-2)-induced endothelial cell proliferation without affecting endothelial motility; moreover, HPR inhibited growth factor-induced angiogenesis in the CAM assay. Furthermore, a significant antiangiogenic potential of HPR has also been observed in neuroblastoma (NB) biopsy-induced angiogenesis in vivo. We previously demonstrated that supernatants derived from NB cell lines stimulated endothelial cell proliferation. In the present study, we found that this effect was abolished when NB cells were incubated in the presence of HPR. VEGF- and FGF-2-specific ELISA assays, performed on both NB cells derived from conditioned medium and cellular extracts, indicated no consistent effect of HPR on the level of these angiogenic cytokines. Moreover, RT-PCR analysis of VEGF and FGF-2 gene expression confirmed the above lack of effect. HPR was also able to significantly repress the spontaneous growth of endothelial cells, requiring at least 48-72 hr of treatment with HPR, followed by a progressive accumulation of cells in G(1) at subsequent time points. Finally, immunohistochemistry experiments performed in the CAM assay demonstrated that endothelial staining of both VEGF receptor 2 and FGF-2 receptor-2 was reduced after implantation of HPR-loaded sponges, as compared to control CAMs. These data suggest that HPR exerts its antiangiogenic activity through both a direct effect on endothelial cell proliferative activity and an inhibitory effect on the responsivity of the endothelial cells to the proliferative stimuli mediated by angiogenic growth factors.

Topics: Adenocarcinoma; Adrenal Glands; Animals; Anticarcinogenic Agents; Antineoplastic Agents; Cell Cycle; Cell Division; Cell Line; Cell Movement; Chick Embryo; Chorion; Endometrial Neoplasms; Endothelial Growth Factors; Endothelium; Enzyme-Linked Immunosorbent Assay; Female; Fenretinide; Fibroblast Growth Factor 2; Flow Cytometry; Humans; Immunohistochemistry; Kinetics; Lymphokines; Neovascularization, Pathologic; Neuroblastoma; Reverse Transcriptase Polymerase Chain Reaction; Time Factors; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Previous investigations have demonstrated that a synthetic retinoid, N-(4-hydroxyphenyl) retinamide (4-HPR), inhibits the invasion of prostate adenocarcinoma in vitro. Urokinase-type plasminogen activator (uPA) is a prerequisite for tumor invasion. The purpose of this study was to evaluate the effects of 4-HPR on uPA and plasminogen activator inhibitor-1 (PAI-1) in prostate cancer. Human prostate adenocarcinoma cell lines, TSU-PR1 and PC3, were grown in serum-free media containing 4-HPR. Cellular mRNA and protein were subsequently extracted. Northern blot analysis, enzyme-linked immunosorbent assay (ELISA) and chromogenic functional analysis were performed on the samples. Administration of 10(-6) M 4-HPR for 3 days resulted in an increase in uPA mRNA expression (TSU-PR1: 391%, PC3: 356%), and a simultaneous increase in PAI-1 mRNA expression (TSU-PR1: 217%, PC3: 235%) was observed. ELISA concomitantly demonstrated a significant increase (p < 0.05) in uPA protein in the conditioned media (TSU-PR1: 134%, PC3: 139%) and cell lysates (TSU-PR1: 284%, PC3: 255%). Both cell lines demonstrated a significant increase (p < 0.05) in PAI-1 protein in the conditioned media (TSU-PR1: 152%, PC3: 167%) and cell lysates (TSU-PR1: 170%, PC3: 222%). Concentrations below 10(-6) M failed to alter the protein production of either uPA or PAI-1. The functional uPA assay demonstrated a reduction of the proteolytic activity of uPA (TSU-PR1: 13%, PC3: 7%) in cell lysates of 10(-6) M 4-HPR (p < 0.05), while there was minimal uPA activity in the conditioned media. 4-HPR stimulates a paradoxical increase in uPA and PAI-1, but the anti-invasive effects of 4-HPR are consistent with the increase in both uPA and PAI-1, resulting in an overall reduction of functional uPA activities.

Topics: Adenocarcinoma; Antineoplastic Agents; Cycloheximide; Fenretinide; Gene Expression; Humans; Male; Plasminogen Activator Inhibitor 1; Prostatic Neoplasms; Protein Synthesis Inhibitors; RNA Stability; RNA, Messenger; Tumor Cells, Cultured; Urokinase-Type Plasminogen Activator

We have previously reported that the retinoids, 4-(hydroxyphenyl)retinamide (4-HPR) and 9-cis-retinoic acid (RA) prevented azoxymethane (AOM)-induced colon tumors and along with 2-(carboxyphenyl)retinamide (2-CPR) prevented aberrant crypt foci (ACF). In this study, we evaluated the effect of 2-CPR on AOM-induced colon tumors and the effect of the three retinoids on apoptosis and cell proliferation. Male F344 rats were administrated 15 mg/kg AOM at weeks 7 and 8 of age. 2-CPR (315 mg/kg) was administered in the diet starting either 1 week before or at week 12 after the first dose of AOM. The rats continued to receive the 2-CPR until killed at week 46. Unlike the demonstrated prevention of colon cancer by the other two retinoids, both dosing schedules of 2-CPR resulted in an approximate doubling of the yield of colon tumors. In adenomas, 2-CPR, 4-HPR and 9-cis-RA were equally effective in reducing mitotic activity, while only 4-HPR and 9-cis-RA but not 2-CPR enhanced apoptosis. When administered for only the 6 days prior to killing 4-HPR but not 2-CPR decreased the Mitotic Index and increased the Apoptotic Index in adenomas. In non-involved crypts, chronic exposure to 4-HPR and 9-cis-RA in contrast to 2-CPR reduced the Mitotic Index and enhanced the Apoptotic Index. In concurrence with our previous study, both 2-CPR and 4-HPR were very potent in preventing ACF when administered in the diet starting 1 week before the first dose of AOM and continuing for the 5 weeks of the study. Hence, unlike the other two retinoids, 2-CPR, although very potent in preventing ACF, enhanced rather than prevented AOM-induced colon cancer. Furthermore, our results suggest that the effect of 2-CPR on tumor yield is different from 4-HPR and 9-cis-RA because, unlike them, it does not enhance apoptosis.

Topics: Adenocarcinoma; Adenoma; Animals; Anticarcinogenic Agents; Apoptosis; Azoxymethane; Body Weight; Carcinogens; Colon; Colonic Neoplasms; Drug Screening Assays, Antitumor; Fenretinide; Male; Precancerous Conditions; Rats; Rats, Inbred F344; Tretinoin

In order to better understand the mechanisms that underlie the antiproliferative effect of retinoids, we have examined the response of human carcinoma cell lines to all-trans retinoic acid (RA) and N-(4-hydroxyphenyl) retinamide (4HPR) in terms of cell growth, apoptosis and regulation of retinoic acid receptors (RARs) and retinoid X receptors (RXRs) mRNA. GLC82 (lung adenocarcinoma), BGC823 (stomach adenocarcinoma) and EC109 (esophageal squamous carcinoma) cells were treated with 10 microM of RA or 4HPR for various length of time and analyzed. The results show that growth inhibition by RA and 4HPR in GLC82 and BGC823 cells correlates with the induction of RARbeta2 gene, whereas RA resistance in EC109 cells parallels loss of RARbeta2 induction. Exogenous RARbeta2 expression did not restore RA responsiveness in EC109 cells, but potentiated 4HPR-induced growth inhibition, suggesting that 4HPR acts at least in part via the RARbeta receptor. We speculate that the loss of RARbeta2 inducibility in EC109 cells may be due to an unknown repressor.

Topics: Adenocarcinoma; Antineoplastic Agents; Cell Division; Drug Resistance, Neoplasm; Esophageal Neoplasms; Fenretinide; Humans; Lung Neoplasms; Neoplasms; Receptors, Retinoic Acid; Retinoid X Receptors; Stomach Neoplasms; Transcription Factors; Transfection; Tretinoin; Tumor Cells, Cultured

Topics: Adenocarcinoma; Colonic Neoplasms; Cyclooxygenase 1; Cyclooxygenase 2; Dinoprostone; Fenretinide; Gene Expression Regulation, Neoplastic; Humans; Isoenzymes; Membrane Proteins; Prostaglandin-Endoperoxide Synthases; RNA, Messenger; Tetradecanoylphorbol Acetate; Transcription, Genetic; Tumor Cells, Cultured

The synthetic retinoid N-(4-hydroxyphenyl) retinamide (4-HPR) has been demonstrated to inhibit the development of primary and metastatic neoplasms in several animal models. In order to investigate the effect of 4-HPR on human prostate adenocarcinoma, we designed a series of in vitro experiments with the PC3 cell line to evaluate effects on proliferation, cell cycle kinetics, and c-myc mRNA expression. 4-HPR demonstrated cytotoxicity only at the supraphysiologic concentration of 10.0 microM. However, asynchronously growing cells exposed to 1 microM 4-HPR demonstrated a 51% reduction in proliferation rate, associated with an accumulation of cells in the G0/G1 phase of the cell cycle. PC3 cells synchronized with serum deprivation or aphidicolin exhibited significant decreases in DNA synthesis when treated with 1 microM 4-HPR. Additionally, these cells were found to accumulate in G0/G1 and S phase. Northern blots indicated a significant decrease in c-myc mRNA expression in asynchronously growing cells with continuous administration of 1 microM 4-HPR for 6 days. These data suggest that 4-HPR can inhibit growth of PC3 cells as a consequence of a block in cell cycle transition from G1 to S phase at a concentration of 1 microM, and that this inhibition is associated with a suppression of c-myc gene expression.

Topics: Adenocarcinoma; Antineoplastic Agents; Blotting, Northern; Cell Cycle; Cell Division; Cell Line; DNA, Neoplasm; Fenretinide; Flow Cytometry; Gene Expression; Genes, myc; Humans; Male; Prostatic Neoplasms; RNA, Messenger; Thymidine; Time Factors; Tumor Cells, Cultured

N-4-Hydroxyphenylretinamide (fenretinide or 4HPR), a derivative of retinoic acid, has been demonstrated to decrease the development of prostate cancer in a rat carcinogenesis model. This study was undertaken to determine if 4HPR is an effective agent for the treatment of established prostate cancer. In vitro, 4HPR was cytotoxic to rat and human prostate cancer cells as well as endothelial cells. Utilizing three different angiogenesis inhibition assays, it was demonstrated that 4HPR inhibited angiogenesis as well as endothelial cell motility and tubule formation. In vivo, 4HPR inhibited prostate cancer growth in a significant manner. These findings suggest that 4HPR may be a potent inhibitor of early prostate cancer growth.

Topics: Adenocarcinoma; Animals; Cell Division; Endothelium, Vascular; Fenretinide; Humans; In Vitro Techniques; Male; Neoplasm Transplantation; Neovascularization, Pathologic; Prostatic Neoplasms; Rats; Tumor Cells, Cultured

Fenretinide or N-(4-hydroxyphenyl) retinamide (4HPR) is a synthetic retinoid currently being tested clinically, which can inhibit the development and the growth of breast and prostate cancers in rodents. The efficacy of 4HPR alone and in combination with cisplatin was tested against the human ovarian carcinoma IGROV-1 xenograft i.p. Administration p.o. of 4HPR was not effective, whereas intracavitary treatment significantly increased the survival time of treated mice. It also enhanced the antitumor activity of cisplatin. These findings suggest that 4HPR may be an active agent against epithelial ovarian tumors.

Topics: Adenocarcinoma; Animals; Cisplatin; Drug Screening Assays, Antitumor; Drug Synergism; Female; Fenretinide; Humans; Mice; Mice, Nude; Ovarian Neoplasms; Transplantation, Heterologous

We report for the first time that a synthetic retinoid, N-(4-hydroxyphenyl)retinamide, can prevent the development of both primary and metastatic tumors in an animal model of metastasizing primary prostate cancer. Prostatic adenocarcinomas were induced in high incidence in Lobund-Wistar rats by initiation with methylnitrosourea i.v. and promotion with testosterone. Feeding of N-(4-hydroxyphenyl)retinamide to these rats during the latency period markedly diminished the final incidence of both primary and metastatic prostate carcinomas.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Fenretinide; Male; Neoplasm Metastasis; Prostatic Neoplasms; Rats; Rats, Mutant Strains; Tretinoin

Tumor cells of transplanted prostate adenocarcinoma-III (PA-III) spread with very high frequency from the extravascular implant site through ipsilateral lymphatic channels to the lungs in which they produce visible focal tumors. The latter enlarge, coalesce and eventually kill the host. This system was used to demonstrate the effect of a retinoid on metastasis. Lobund-Wistar (L-W) rats were administered 1 mmol 4-HPR/kg diet L-485, and control rats received the same diet without 4-HPR. After an interval, all rats were inoculated subcutaneously with PA-III cells. When examined at autopsy, all rats had developed an anticipated tumor at the implant site. However, the numbers of focal PA-III tumors in the lungs were significantly reduced among the 4-HPR-treated rats compared to the control rats (P = 0.002).

Topics: Adenocarcinoma; Animals; Female; Fenretinide; Male; Neoplasm Metastasis; Neoplasm Transplantation; Prostatic Neoplasms; Rats; Rats, Inbred Strains; Tretinoin

Virgin Sprague--Dawley rats received a single i.v. injection of 40 mg N-methyl-N-nitrosourea (MNU)/kg body wt. at 50 days of age. After the first palpable mammary tumor reached 10 mm in size, the animals were sequentially allocated to one of 4 groups: (I) placebo diet, (II) 10 micrograms tamoxifen s.c. 3 times per week, (III) 3 mmol N-(4-hydroxyphenyl)retinamide (4-HPR)/kg diet, or (IV) both (II) and (III). Weekly measurements of initial tumors and subsequent tumors were made throughout the study. 4-HPR administration resulted in a complete regression (non-palpable state) of the first mammary tumor in 6 animals (22%) and partial regression or nonprogression in 5 others (19%). Tamoxifen alone induced only partial response in 9 animals (33%). 4-HPR and tamoxifen resulted in 19% total and 26% partial response. The data suggests therapeutic value of 4-HPR in MNU-induced rat mammary carcinoma.

Topics: Adenocarcinoma; Animals; Antineoplastic Combined Chemotherapy Protocols; Female; Fenretinide; Mammary Neoplasms, Experimental; Methylnitrosourea; Rats; Remission Induction; Tamoxifen; Tretinoin