alitretinoin and Uterine-Cervical-Neoplasms

9-Cis-retinoic acid (aliretinoin) is a pan-retinoid receptor agonist and has been demonstrated in preclinical models to have potent chemoprevention effects. The purpose of this study was to determine the utility of using aliretinoin as a chemoprevention agent in cervical dysplasia. Patients with histological evidence of cervical intraepithelial neoplasia (CIN) 2/3 were randomized in a double-blind manner to receive high-dose aliretinoin (50 mg), low-dose of aliretinoin (25 mg), or placebo daily for 12 weeks. Compliance and side effects were monitored at various time points during therapy. At the completion of therapy, all of the patients underwent a loop procedure. Histology of pretreatment biopsies was compared with that of loop specimens. One-hundred and fourteen patients with CIN 2/3 were enrolled in the study. In the 112 patients evaluable for toxicity, headache was the most common clinical side effect and was experienced more frequently (74%) in the high-dose aliretinoin group. Eight patients withdrew from the study before completion of study medication because of unacceptable side effects. In the 104 patients evaluable for efficacy, there was no statistical difference in the rate of regression among the placebo (32%), the low-dose aliretinoin (32%), and the high-dose aliretinoin (36%) groups. (P = not significant; power 0.06). Aliretinoin at these dosages and this schedule does not appear to result in significant regression rates in CIN 2/3 patients when compared with placebo. Headache is encountered frequently and may thwart efforts to increase the dose or duration of aliretinoin in future cervical cancer chemoprevention studies. The rate of histological regression in biopsied CIN 2/3 patients is high even over a short time interval, and emphasizes the importance of having a placebo arm and an adequate sample size in cervical dysplasia chemoprevention studies.

Topics: Adolescent; Adult; Alabama; Alitretinoin; Antineoplastic Agents; Biomarkers; Chemoprevention; Cholesterol, HDL; Dose-Response Relationship, Drug; Double-Blind Method; Drug Evaluation; Female; Hemoglobins; Humans; Patient Compliance; Severity of Illness Index; Treatment Outcome; Tretinoin; Triglycerides; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms; Women's Health

Current therapy for cervical cancer includes radiation therapy. Retinoic acid (RA) can increase the sensitivity of cervical cancer cell lines to radiation. The mechanism of this sensitization may not involve the p53 protein because the human papillomavirus (HPV) E6 protein, which is present in the majority of cervical cancers, promotes p53 degradation. The objective of this study was to determine if p53 is involved in the mechanism of RA radiosensitization.. The effects of radiation on cervical (SiHa, CC-1, and C33a) and vulvar (SW962) cancer cell lines under various experimental conditions were evaluated using clonogenic, Coulter Counter, electrophoretic mobility shift (EMSA) and a multi-probe RNase protection assay of p53-inducible genes.. RA (5 microM 9-cis-RA) radiosensitized the SiHa and CC-1 cell lines that contain HPV-degraded p53, but did not radiosensitize the SW962 cell line, which is HPV negative and contains wild-type p53, nor the C33a cell line, which contains mutant p53 (R273C). Expression of mutant p53 (R273H) in SiHa cells increased the growth rate, but did not prevent RA-induced differentiation or radiosensitization at clinically relevant doses. Inhibition of p53 transactivation with pifithirin alpha did not prevent RA radiosensitization of SiHa at 5 Gy. RA repressed c-fos mRNA expression in control and irradiated SiHa cultures, but did not repress bcl-x(L), p53, GADD45, p21, bax, bcl-2, or mcl-1 mRNA expression.. The mechanism of RA radiosensitization does not require functional p53 and may involve c-fos in cervical cancer cell lines.

Topics: Alitretinoin; Benzothiazoles; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Combined Modality Therapy; DNA Damage; Dose-Response Relationship, Radiation; Female; Genes, fos; Humans; Radiation-Sensitizing Agents; Thiazoles; Toluene; Transfection; Tretinoin; Tumor Suppressor Protein p53; Uterine Cervical Neoplasms

The aim of this study was to determine whether receptor-dependent and receptor-independent retinoids sensitize cervical cancer cells to clinically relevant doses of concurrent radiation and cisplatin.. The clonogenic assay was performed on SiHa cervical carcinoma cultures treated with 5 microM 9-cis-retinoic acid (RA) or 3 microM 4-HPR for 3 days prior to and following concurrent treatment with 3 microM cisplatin and 2 Gy of Co(60) radiation.. Neither 9-cis-RA nor 4-HPR significantly decreased survival for radiation only or cisplatin only (t test: P < 0.05), but both significantly decreased survival of cultures receiving concurrent chemoradiation (t test: 9-cis-RA P = 0.045; 4-HPR P = 0.027).. Both receptor-dependent and receptor-independent retinoids enhance concurrent chemoradiation effects in vitro.

Topics: Alitretinoin; Antineoplastic Combined Chemotherapy Protocols; Cell Survival; Cisplatin; Combined Modality Therapy; Drug Synergism; Female; Fenretinide; Humans; Receptors, Retinoic Acid; Tretinoin; Tumor Cells, Cultured; Uterine Cervical Neoplasms

Retinoic acid (RA) has been shown to radiosensitize some tumor cell lines. RA regulates gene expression through nuclear receptors that bind to retinoic acid response elements in gene promoters and that inhibit activator protein-1 (AP-1) transcription factor activity.. The aim of this study was to determine if the mechanism of radiosensitization of the CC-1 human cervical carcinoma cell line by 9-cis-RA (9cRA) involves repression of AP-1 activity.. The CCA reporter cell line was established from CC-1 by permanent transfection with the ColCAT reporter plasmid which consists of the chloramphenicol acetyltransferase (CAT) gene under the control of the AP-1-responsive collagenase gene promoter. CCA cultures were treated with various combinations of 9cRA, 60Co radiation, and an AP-1 inducer called O-tetradecanoylphorbol 13-acetate (TPA). Cultures were then evaluated in parallel for CAT expression as a measure of AP-1 activity and for clonogenic survival as a measure of radiosensitization.. The CCA reporter line exhibited a radiation dose-responsive induction of AP-1 activity that was decreased by 5 microM 9cRA and increased by 50 ng/ml TPA. Simultaneous treatment with TPA and 9cRA prevented 9cRA repression of AP-1 and resulted in AP-1 activity above basal level. The 9cRA radiosensitized CC-1 cultures with a dose modification factor of 1.5. The survival of cultures treated simultaneously with TPA and 9cRA was statistically identical to that of cultures treated with 9cRA alone.. Although TPA prevented AP-1 repression by 9cRA, it did not prevent radiosensitization in CCA cultures, therefore the mechanism of radiosensitization of CCA by 9cRA is independent of AP-1 repression.

Topics: Alitretinoin; Antineoplastic Agents; Dose-Response Relationship, Drug; Female; Gene Expression Regulation, Neoplastic; Humans; Radiation-Sensitizing Agents; Tetradecanoylphorbol Acetate; Transcription Factor AP-1; Tretinoin; Tumor Cells, Cultured; Uterine Cervical Neoplasms

Retinoids, including natural vitamin A and its analogs, have been closely studied as chemopreventive drugs. The mechanism of action of retinoids, however, is not completely understood. Our study evaluated the effects of all-trans (high affinity ligand for both RAR and RXR receptors) and 9-cis retinoic acid (binds only with RXR receptors) on E6-E7 transcription, cell proliferation, cell cycle distribution, and p53 expression in CaSki cells, a cell line derived from cervical carcinoma containing 600 copies of the HPV-16 genome. Using quantitative RT-PCR analysis, we found that CaSki cells treated with all trans retinoic acid (ATRA) for seven days had a remarkably low level of E6-E7 transcription at 10(-5) M to 10(-9) M concentrations. A smaller inhibitory effect was observed on the E6-E7 transcription at a concentration of 10(-5) M with only 9-cis retinoic acid. Flow cytometric analysis revealed that cells treated with both all trans and 9-cis RA showed an increase in the mean percentage (93.5% and 86.1% respectively) of cells in the G1 phase as compared to untreated CaSki cells (55%) and normal keratinocytes (58%). The percentage of cells in the S phase decreased from a mean percentage of 28 and 26.5 to 5.8 and 5, respectively, after treatment with all trans retinoic acid and 9-cis retinoic acid. An increase in the level of immunophenotypic expression of wild type p53 was also noted after treatment with all trans retinoic acid and 9-cis retinoic acid. All trans and 9-cis retinoic acid may act on highly proliferating tumor cells by initially arresting DNA synthesis and inducing G1 arrest. In addition, they may be inducing a p53 dependent cell cycle arrest and thus suggests that all-trans and 9-cis retinoic acid may have a cytostatic effect rather than a cytotoxic effect on CaSki cells. The increased expression of p53 positive cells and the inhibition of E6/E7 transcription after treatment with these retinoids may indicate the potential role of all trans and 9-cis retinoic acid as a cell cycle regulator and an antiviral chemoprevention agent.

Topics: Alitretinoin; Cell Cycle; Female; Flow Cytometry; Humans; Oncogene Proteins, Viral; Papillomavirus E7 Proteins; Polymerase Chain Reaction; Repressor Proteins; RNA, Messenger; Tretinoin; Tumor Cells, Cultured; Uterine Cervical Neoplasms

Retinoic acid receptor (RAR) active retinoids have proven therapeutically useful for treating certain cancers and dermatological diseases. Herein, we describe the discovery of two new RAR active trienoic acid retinoids, (2E,4E,6E)-7-(3,5-di-tert-butylphenyl)-3-methylocta-2, 4,6-trienoic acid (10a, ALRT1550) and (2E,4E,6Z)-7-(3,5-di-tert-butylphenyl)-3-methylocta-2, 4,6-trienoic acid (10b, LG100567). ALRT1550 is a RAR selective retinoid which exhibits exceptional potency in both competitive binding and cotransfection assays. Moreover, it is the most potent antiproliferative retinoid described to date and thus has implications for the treatment of certain cancers. LG100567 is a potent panagonist which activates both RARs and retinoid X receptors.

Topics: Antineoplastic Agents; Cell Division; Drug Screening Assays, Antitumor; Female; Humans; Molecular Structure; Receptors, Retinoic Acid; Retinoid X Receptors; Retinoids; Thymidine; Transcription Factors; Tumor Cells, Cultured; Uterine Cervical Neoplasms

Topics: Alitretinoin; Animals; Anticarcinogenic Agents; Antineoplastic Agents; Breast Neoplasms; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Drug Approval; Female; Humans; Neoplasms, Experimental; Rats; Research Design; Tretinoin; Uterine Cervical Neoplasms