retinol-palmitate and Adenocarcinoma

Lung cancer is the major cause of death in industrialized western societies. Its link to tobacco abuse is well established and efforts should be made to eliminate this potent environmental carcinogen. The concept of chemoprevention, the use of agents to inhibit and reverse lung cancer carcinogenesis, has great appeal. The CARET study, conducted in 18,000 high-risk smokers in the US, found that a combination of beta-carotene and retinyl palmitate resulted in a 28% increase in the incidence of lung cancer. A similar study conducted in Finland, the ATBC trial utilizing alpha tocopherol and beta-carotene, had similar findings for the group taking beta-carotene. These two trials have caused a rethinking of the use of natural compounds as chemoprevention agents. These agents should no longer be regarded as harmless, but as having potential toxicities. A new approach in the chemoprevention of cancer has been the concept of surrogate endpoints, biological changes that are on the pathway to cancer. Trials are underway to determine what are appropriate surrogate endpoints for lung cancer chemoprevention trials.

Topics: Adenocarcinoma; Adolescent; Adult; Aged; Anticarcinogenic Agents; beta Carotene; Carotenoids; Chromosomes, Human, Pair 3; Clinical Trials as Topic; Cocarcinogenesis; Cytochrome P-450 CYP1A1; Diterpenes; Female; Flavonoids; Genetic Predisposition to Disease; Glutathione Transferase; Humans; Inactivation, Metabolic; Incidence; Lung Neoplasms; Lycopene; Male; Middle Aged; Polymorphism, Genetic; Precancerous Conditions; Retinoids; Retinyl Esters; Risk Factors; Selenium; Smoking; Smoking Prevention; Trace Elements; Treatment Outcome; Vitamin A; Vitamin E

Because of the poor response of pancreatic cancer to conventional therapy, the authors performed a phase II pilot study to evaluate whether beta-interferon and retinoids, added to active chemotherapeutic agents, could increase response rate and survival in a group of patients who had metastatic disease. Twenty-three chemotherapy-naive patients were treated as follows: epirubicin, 60 mg/m2, and mitomycin C, 10 mg/m2, intravenously on day 1; folinic acid, 200 mg/m2, and 5-fluorouracil (5-FU), 370 mg/m2, intravenously for 5 consecutive days. beta-Interferon, 1 x 10(6) IU/m2, subcutaneously three times a week, and retinol palmitate, 50,000 IU orally twice a day, were given between chemotherapy cycles. Patients having responses and disease stabilization were maintained with the same dose of beta-interferon and retinol palmitate. Treatment was given every 4 weeks for four courses or until onset of progression. A median of three courses of chemotherapy was delivered to each patient. All patients were evaluable. Eight patients responded (35%) and 8 (35%) had stable disease. Median time to progression and survival for all patients were, respectively, 6.1 months and 11 months. Toxicity was severe: 60% of patients had hematologic toxicity, 40% had gastrointestinal toxicity, 13% had cardiac toxicity, and 1 patient had a hemolitic-uremic syndrome. The combination of chemotherapy, beta-interferon, and retinoids shows activity in metastatic pancreatic carcinoma. Toxicity was high but patients who had responses and disease stabilization had prolonged symptom palliation.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Diterpenes; Epirubicin; Female; Fluorouracil; Humans; Interferon-beta; Leucovorin; Male; Middle Aged; Mitomycin; Pancreatic Neoplasms; Retinyl Esters; Survival Rate; Vitamin A

Although gastrointestinal toxicity is one of the most common side effects of anticancer therapy, the diagnosis and assessment of this toxicity still depend mostly on anamnestic data. Measurement of intestinal permeability is one of potential methods of non-invasive laboratory evaluation of gastrointestinal toxicity. The aim of the present study was to investigate intestinal permeability, vitamin A absorption, serum alpha-tocopherol, and urinary neopterin in patients with rectal carcinoma treated with chemoradiation. We have studied intestinal permeability, vitamin A absorption, serum alpha-tocopherol, and urinary neopterin in 17 patients with rectal carcinoma treated with chemoradiation. Urinary lactulose, mannitol, and xylose were measured by capillary gas chromatography, and serum alpha-tocopherol, retinol, retinyl esters, and urinary neopterin were determined by high-performance liquid chromatography. Lactulose/mannitol ratio was increased 5 and 6 weeks after the start of the treatment. Serum alpha-tocopherol was decreased significantly throughout the course of treatment, but no significant changes were observed in postprandial serum concentrations of retinyl esters or in the concentrations of urinary neopterin. A correlation was observed between baseline parameters of intestinal permeability and urinary neopterin. The measurement of intestinal permeability using the lactulose/mannitol test may represent a sensitive tool in the detection of changes associated with chemoradiation in patients with rectal carcinoma. The therapy is also associated with a decrease of alpha-tocopherol.

Topics: Adenocarcinoma; Aged; alpha-Tocopherol; Antimetabolites, Antineoplastic; Antioxidants; Carbohydrates; Chromatography, Gas; Chromatography, High Pressure Liquid; Combined Modality Therapy; Dietary Carbohydrates; Diterpenes; Female; Fluorouracil; Humans; Intestinal Absorption; Male; Middle Aged; Neopterin; Radiotherapy, High-Energy; Rectal Neoplasms; Retinyl Esters; Vitamin A

Epidemiological studies have shown an inverse relationship between dietary vitamin A intake and the risk of developing lung cancer. The aim of this study was to investigate the vitamin A status in patients with lung cancer, by determining the serum levels of retinoic acid, retinol and retinyl palmitate.. In total, 36 patients with lung cancer and 27 controls were assessed. Of the patients 14 had squamous cell carcinoma, 3 adenocarcinoma, 15 non-small cell lung cancer and 4 small cell lung cancer. Serum retinoic acid, retinol and retinyl palmitate levels were determined with HPLC and UV detection, after liquid extraction.. Serum retinol levels did not differ between patients (733.5 +/- 326.4 ng/mL) and controls (734.5 +/- 337.1 ng/mL). The retinyl palmitate concentration tended to be lower in patients (14.3 +/- 9.7 ng/mL) than in controls (16.7 +/- 13.7 ng/mL). The serum retinoic acid levels were significantly lower in patients (1.9 +/- 0.6 ng/mL) than in controls (2.5 +/- 1.1 ng/mL, P < 0.05). A positive correlation was observed between the retinol and retinoic acid levels and retinyl palmitate and retinoic acid levels.. The lower levels of retinoic acid in patients with lung cancer suggest there may be a deficiency or impairment in retinol metabolism in these patients. Further studies with larger numbers of patients are needed to evaluate the possible relationship between serum retinoid levels and lung cancer.

Topics: Adenocarcinoma; Aged; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Chromatography, High Pressure Liquid; Disease Progression; Diterpenes; Female; Humans; Lung Neoplasms; Male; Prognosis; Retinyl Esters; Risk Factors; Tretinoin; Vitamin A

The mechanism by which vitamin A prevents or delays chemical carcinogenesis remains unclear. In addition to these antimutagenic and antiproliferative activities, vitamin A seems able to induce programmed cell death. In this study, we assess the suggested role of vitamin A on the in vitro apoptosis induction in a rat colonic tumor cell line. Several concentrations of retinyl palmitate were added in the culture media. We observed cell proliferation by measuring the (3H)thymidine incorporation, cell differentiation by measuring the intestinal alkaline phosphatase expression, and apoptosis induction by DNA fragmentation and morphological evolution of adherent and floating cells. The results show that vitamin A decreases (3H)thymidine incorporation after 1 day of treatment, induces alkaline phosphatase expression, and increases the number of cells falling in apoptosis. This report confirms the role of vitamin A on the induction of cell differentiation, on the inhibition of cell proliferation and shows the vitamin A capacity to induce apoptosis. These results could be attractive to prevent development of colon cancer by vitamin A supplemented diets.

Topics: Adenocarcinoma; Alkaline Phosphatase; Animals; Apoptosis; Cell Differentiation; Cell Division; Colonic Neoplasms; Culture Media; Diterpenes; DNA Fragmentation; Rats; Retinyl Esters; Tumor Cells, Cultured; Vitamin A

Lower lobe origin and histologic diagnosis of adenocarcinoma have been described as useful parameters for attributing lung cancer to prior asbestos exposure. To assess whether these characteristics differed between asbestos-exposed individuals and smokers, we evaluated lobe of origin and histologic type of tumors in 78 asbestos-exposed and 214 nonexposed heavy smokers developing lung cancer during the Carotene and Retinol Efficacy Trial (CARET), a prospective cancer chemoprevention trial. Most tumors in both cohorts, regardless of radiographic fibrosis at baseline, originated in upper lobes, representing 67% in asbestos-exposed and 80% in smokers, respectively (adjusted OR for lower lobe = 1.41; 95% CI = 0.69-2.91). Adenocarcinoma represented 32% of lung tumors in the asbestos cohort, and 30% in the smoking cohort (adjusted OR = 0.78; 95% CI = 0.40-1.55), and was inversely associated with radiographic fibrosis (adjusted OR = 0.19; 95% CI = 0.06-0.62). We conclude that neither anatomic site nor histologic cell type of tumors distinguishes effectively between smoking and asbestos as causal factors in development of lung cancer.

Topics: Adenocarcinoma; Anticarcinogenic Agents; beta Carotene; Causality; Confounding Factors, Epidemiologic; Diterpenes; Double-Blind Method; Female; Humans; Lung Neoplasms; Male; Middle Aged; Multicenter Studies as Topic; Occupational Diseases; Occupational Exposure; Prospective Studies; Pulmonary Fibrosis; Randomized Controlled Trials as Topic; Retinyl Esters; Smoking; Vitamin A

F344 rats were given saline, vitamin A placebo or vitamin A analogues orally for 4 consecutive days. The following day they were killed and their alveolar macrophages (AM phi) were harvested by lavage. The functional integrity of the AM phi was determined by their capacity to phagocytize opsonized SRBC and to kill syngeneic adenocarcinoma cell lines nonspecifically. Results showed that 4 days treatment with greater than 100 IU of vitamin A as retinyl palmitate per gram body weight rendered the AM phi tumoricidal against syngeneic mammary adenocarcinoma cell lines (MADB-100 and MADB-200) and that AM phi activated with retinyl palmitate showed increased ability to phagocytize opsonized SRBC. Other retinoids, such as retinoic acid and retinol, had the same effect of inducing tumoricidal activity in rat AM phi. AM phi harvested from normal rats were also rendered tumoricidal by direct interaction with greater than 10(3) IU ml-1 of retinyl palmitate for 24 h in vitro. Thus, vitamin A at high doses can increase the phagocytic and tumoricidal activities of rat AM phi.

Topics: Adenocarcinoma; Animals; Cells, Cultured; Cytotoxicity, Immunologic; Diterpenes; Dose-Response Relationship, Immunologic; Macrophage Activation; Macrophages; Male; Mammary Neoplasms, Experimental; Phagocytosis; Pulmonary Alveoli; Rats; Rats, Inbred F344; Retinyl Esters; Tretinoin; Vitamin A