alitretinoin and Body-Weight

The purpose of this study was to examine the neurorestorative effect of delayed 9 cis retinoic acid (9cRA) treatment for stroke. Adult male rats received a 90-min right distal middle cerebral artery occlusion (dMCAo). Animals were separated into two groups with similar infarction sizes, based on magnetic resonance imaging on day 2 after dMCAo. 9cRA or vehicle was given via an intranasal route daily starting from day 3. Stroke rats receiving 9cRA post-treatment showed an increase in brain 9cRA levels and greater recovery in motor function. 9cRA enhanced the proliferation of bromodeoxyuridine (+) cells in the subventricular zone (SVZ) and lesioned cortex in the stroke brain. Using subventricular neurosphere and matrigel cultures, we demonstrated that proliferation and migration of SVZ neuroprogenitor cells were enhanced by 9cRA. Our data support a delayed and non-invasive drug therapy for stroke. Intranasal 9cRA can facilitate the functional recovery and endogenous repair in the ischemic brain.

Topics: Alitretinoin; Animals; Body Weight; Bone Morphogenetic Protein 7; Cell Movement; Cell Proliferation; Cerebral Cortex; Disease Models, Animal; Immunohistochemistry; Lateral Ventricles; Magnetic Resonance Imaging; Male; Motor Activity; Rats; Stroke

Chemopreventive activities of all-trans retinoic acid (AtRA), 9-cis retinoic acid (9cRA), retinol (ROL) and beta-carotene (betaC) were evaluated during hepatocarcinogenesis. Rats received 1 mg/100 g body wt AtRA (AtRA group), 9cRA (9cRA group), ROL (ROL group), 7 mg/100 g body wt betaC (betaC group) or corn oil (CO group, controls). Hepatocyte nodule incidence was reduced (P < 0.05) in betaC group (46%), but not (P > 0.05) in AtRA (92%), 9cRA (92%) and ROL (82%) groups, compared with the CO group (100%). Multiplicity of these preneoplastic lesions (PNL) was different (P < 0.05) between CO group (44 +/- 9) and 9cRA (11 +/- 4), ROL (7 +/- 3) and betaC (4 +/- 2) groups, except for AtRA group (27 +/- 9; P > 0.05). Number/cm(2) liver section, mean area (mm(2)) and percent liver section area occupied by total (persistent + remodeling) placental glutathione S-transferase (GST-P) positive PNL was reduced (P < 0.05) in AtRA (107 +/- 13; 0.12 +/- 0.06; 13.9 +/- 3.9), 9cRA (71 +/- 12; 0.12 +/- 0.06; 6.8 +/- 2.2), ROL (96 +/- 13; 0.11 +/- 0.22; 6.8 +/- 2.0) and betaC (106 +/- 13; 0.08 +/- 0.03; 10.8 +/- 2.5) groups compared with CO group (166 +/- 14; 0.18 +/- 0.09; 28.6 +/- 5.2). Percent of remodeling GST-P positive PNL was increased (P < 0.05) in 9cRA (92 +/- 1), ROL (96 +/- 1) and betaC (93 +/- 1) groups, but not (P > 0.05) in AtRA group (90 +/- 2), compared with the CO group (86 +/- 1). Compared with the CO group, all groups present in PNL reduced (P < 0.05) cell proliferation and no differences (P > 0.05) in apoptosis. DNA damage [comet length (mum)] was reduced (P < 0.05) in ROL (87.9 +/- 2.6) and betaC (89.2 +/- 4.0) groups, but not in AtRA (94.8 +/- 4.1) and 9cRA (94.2 +/- 1.5) groups, compared with the CO group (100.4 +/- 3.9). AtRA, 9cRA, ROL and betaC presented chemopreventive activities against hepatocarcinogenesis. These involve inhibition of cell proliferation, but not induction of apoptosis. Increased remodeling of GST-P positive PNL relates to 9cRA, ROL and betaC actions, while inhibition of DNA damage relates to ROL and betaC actions.

Topics: Alitretinoin; Animals; Antineoplastic Agents; Antioxidants; Apoptosis; beta Carotene; Body Weight; Cell Proliferation; Chemoprevention; Comet Assay; DNA Damage; Glutathione Transferase; Hepatocytes; Incidence; Liver Neoplasms, Experimental; Male; Organ Size; Precancerous Conditions; Rats; Rats, Wistar; Tretinoin; Vitamin A

In most previous studies, the incidence and multiplicity of chemically induced prostate tumors have been used as end points for assessing the efficacy of various chemopreventive agents. In this study, we used prostate intraepithelial neoplasia (PIN) in Noble rats as an intermediate end point to examine the chemopreventive efficacy of two retinoids, 9-cis-retinoic acid (9cRA) and 4-(hydroxyphenyl)retinamide, which in previous studies have shown promising inhibitory effects on various carcinogenesis models. We found that 80-100% of Noble rats treated for 36 weeks with testosterone + 17beta-estradiol developed multiple PIN lesions predominantly in the dorso-lateral prostate, which appears relevant to the place of origin of PIN and carcinoma in the human prostate. 9cRA at 50 or 100 mg/kg diet significantly decreased the multiplicity of PIN, whereas 4-(hydroxyphenyl) retinamide at 392 or 784 mg/kg diet, did not have an inhibitory effect on PIN. Thus, we provide for the first time evidence that the testosterone + 17beta-estradiol-induced PIN in Noble rats could be used as a potential intermediate end point in assessing the efficacy of retinoids and possibly of other agents on prostate carcinogenesis, and that 9cRA alone or in combination with other agents may have clinical promise in preventing the development of prostate cancer in men.

Topics: Alitretinoin; Animals; Anticarcinogenic Agents; Body Weight; Estradiol; Fenretinide; Male; Prostatic Intraepithelial Neoplasia; Prostatic Neoplasms; Rats; Testosterone; Tretinoin

In experimental trials using the N-nitroso-N-methylurea (NMU)-induced rat mammary tumor model, a significant decrease in tumor incidence (to 5%) was observed in rats treated with melatonin and 9-cis-retinoic acid (9 cRA) compared to controls (55%). Although 9cRA alone decreased tumor incidence to 26%, this response did not reach statistical significance. Tumor incidence was significantly inhibited to 20% in the animals that received melatonin and 9cRA on alternating days. Latency to tumor onset was prolonged in animals receiving either of the combination treatments compared with controls, and tumor multiplicity was also significantly decreased.

Topics: Adenocarcinoma; Alitretinoin; Animals; Anticarcinogenic Agents; Antioxidants; Body Weight; Carcinogens; Drug Synergism; Drug Therapy, Combination; Estradiol; Estrogen Receptor alpha; Female; Free Radical Scavengers; Mammary Neoplasms, Experimental; Melatonin; Methylnitrosourea; Organ Size; Rats; Rats, Sprague-Dawley; Receptors, Estrogen; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Tretinoin; Uterus

Neuroblastoma, a childhood tumour of the sympathetic nervous system, may undergo spontaneous differentiation or regression due to apoptosis after no or minimal therapy. However, the majority of neuroblastomas are diagnosed as metastatic tumours with a poor prognosis in spite of intensive multimodal therapy. Vitamin A and its analogues (retinoic acid, RA) play an important role in normal cel lular differentiation and programmed cell death. RA regulates neuroblastoma growth and differentiation in vitro, and has shown activity against human neuroblastoma in vivo.. Recently, 9-cis RA was shown to induce apoptosis in vitro in neuroblastoma using a 5 days short-term treatment and subsequent washout. In the present study, nude rats with human neuroblastoma SH-SY5Y xenografts were treated with 13-cis RA (4 mg po daily), 9-cis RA (5 mg po daily) or the novel analogue Ro 13-6307 (0.3 mg po daily) using either a continuous or short-term schedule.. ALL three different retinoids decreased neuroblastoma growth significantly in terms of tumour weight after 8-12 days when compared to untreated controls (P < 0.05). Minor signs of toxicity in 13-cis RA treated rats were observed. However, severe toxicity with significant weight loss was seen in all rats treated with 9-cis RA and Ro 13-6307. Toxicity was more pronounced with the continuous regimen.. We conclude that different retinoids reduce neuroblastoma tumour growth in vivo. Drug scheduling and dosage may affect both therapeutic efficacy and toxic side effects. Further in vivo studies are warranted, including pharmacokinetic and molecular analyses, before clinical trials with promising retinoids like 9-cis RA and Ro 13-6307 can be started in children with neuroblastoma.

Topics: Alitretinoin; Animals; Antineoplastic Agents; Body Weight; Cell Differentiation; Cell Division; Diarrhea; Drug Administration Schedule; Fatty Acids, Unsaturated; Female; Humans; Isotretinoin; Male; Mice; Neoplasm Transplantation; Neuroblastoma; Rats; Rats, Nude; Tretinoin; Tumor Cells, Cultured; Xenograft Model Antitumor Assays