alitretinoin and Skin-Neoplasms

Kaposi's sarcoma remains the most common cancer in Sub-Saharan Africa and the second most common cancer in HIV-infected patients worldwide. Since the introduction of highly active antiretroviral therapy (HAART), there has been a decline in its incidence.However, Kaposi's sarcoma continues to be diagnosed in HIV-infected patients.. To assess the added advantage of chemotherapy plus HAART compared to HAART alone; and the advantages of different chemotherapy regimens in HAART and HAART naive HIV infected adults with severe or progressive Kaposi's sarcoma.. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and , GATEWAY, the WHO Clinical Trials Registry Platform and the US National Institutes of Health's ClinicalTrials.gov for ongoing trials and the Aegis archive of HIV/AIDS for conference abstracts. An updated search was conducted in July 2014.. Randomised trials and observational studies evaluating the effects of any chemotherapeutic regimen in combination with HAART compared to HAART alone, chemotherapy versus HAART, and comparisons between different chemotherapy regimens.. Two review authors assessed the studies independently and extracted outcome data.We used the risk ratio (RR) with a 95% confidence interval (CI) as the measure of effect.We did not conduct meta-analysis as none of the included trials assessed identical chemotherapy regimens.. We included six randomised trials and three observational studies involving 792 HIV-infected adults with severe Kaposi's sarcoma.Seven studies included patients with a mix of mild to moderate (T0) and severe (T1) Kaposi's sarcoma. However, this review was restricted to the subset of participants with severe Kaposi's sarcoma disease.Studies comparing HAART plus chemotherapy to HAART alone showed the following: one trial comparing HAART plus doxorubicin,bleomycin and vincristine (ABV) to HAART alone showed a significant reduction in disease progression in the HAART plus ABV group (RR 0.10; 95% CI 0.01 to 0.75, 100 participants); there was no statistically significant reduction in mortality and no difference in adverse events. A cohort study comparing liposomal anthracyclines plus HAART to HAART alone showed a non-statistically significant reduction in Kaposi's sarcoma immune reconstitution inflammatory syndrome in patients that received HAART plus liposomal anthracyclines (RR 0.49; 95% CI 0.16 to 1.55, 129 participants).Studies comparing HAART plus chemotherapy to HAART plus a different chemotherapy regimen showed the following: one trial involving 49 participants and comparing paclitaxel versus pegylated liposomal doxorubicin in patients on HAART showed no difference in disease progression. Another trial involving 46 patients and comparing pegylated liposomal doxorubicin versus liposomal daunorubicin showed no participants with progressive Kaposi's sarcoma disease in either group.Studies comparing different chemotherapy regimens in patients from the pre-HAART era showed the following: in the single RCT comparing liposomal daunorubicin to ABV, there was no significant difference with the use of liposomal daunorubicin compared to ABV in disease progression (RR 0.78; 95% CI 0.34 to 1.82, 227 participants) and overall response rate. Another trial involving 178 participants and comparing oral etoposide versus ABV demonstrated no difference in mortality in either group. A non-randomised trial comparing bleomycin alone to ABV demonstrated a higher median survival time in the ABV group; there was also a non-statistically significant reduction in adverse events and disease progression in the ABV group (RR 11; 95% CI 0.67 to 179.29, 24 participants).An additional non-randomised study showed a non-statistically significant overall mortality benefit from liposomal doxorubicin as compared to conservative management consisting of either bleomycin plus vinblastine, vincr. The findings from this review suggest that HAART plus chemotherapy may be beneficial in reducing disease progression compared to HAART alone in patients with severe or progressive Kaposi's sarcoma. For patients on HAART, when choosing from different chemotherapy regimens, there was no observed difference between liposomal doxorubicin, liposomal daunorubicin and paclitaxel.

Topics: Alitretinoin; Antineoplastic Agents; Antiretroviral Therapy, Highly Active; Bleomycin; Doxorubicin; Drug Therapy, Combination; Etoposide; HIV Infections; Humans; Liposomes; Observational Studies as Topic; Randomized Controlled Trials as Topic; Sarcoma, Kaposi; Skin Neoplasms; Tretinoin; Vincristine

In many countries, Kaposi's sarcoma (KS) is the commonest malignancy among individuals infected with the human immunodeficiency virus-1 (HIV) and is a cause of substantial morbidity and mortality.. The aim of this review was to assess the effectiveness of current therapeutic regimens for the treatment of HIV associated KS, with a focus on options that may be available in resource poor settings.. We searched Cochrane HIV/AIDS Group trials register, Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 1, 2002), MEDLINE, EMBASE, AIDSLINE, CINAHL, CANCER LIT, AIDSDRUGS, AIDSTRIALS, African index medicus, physicians data query protocols, United Kingdom Co-ordinating committee on Cancer Research Register of Cancer trials, proceedings and abstracts from AIDS and cancer conferences. The search was conducted between 1st October 2001 and completed 14th December 2002. We also contacted experts in the field of cancer.. Randomised trials of therapy for KS in HIV infected adults.. All reviewers assessed trial quality and extracted data. We contacted study authors for additional information.. Five trials involving 915 people were included. Two trials involving 499 people compared pegylated liposomal doxorubicin (PLD) to a standard regimen among patients with advanced KS were analysed together. There was no difference in mortality between the two regimens RR1.26 (95% confidence interval (CI) 0.83 to 1.91). The response to PLD was superior to that of the control regimen RR 2.16, (95% CI 1.68 to 2.78). Two other trials involving 402 people demonstrated that topical alitretinoin was effective treatment compared to placebo among patients with cutaneous Kaposi's sarcoma. The results were analysed separately due to heterogeneity; (1) the relative risk (RR) was 5.34 (95%CI 2.16 to 13.21) and (2) RR 1.96, 95% CI 1.27 to 3.01). The final trial compared different radiotherapy regimens for treatment of cutaneous KS. The initial complete response of lesions to 20Gy given in 10 fractions or 40Gy in 20 fractions was similar and slightly superior to that of lesions treated with 8Gy as a single fraction, RR 1.58, (95% CI 1.01 to 2.48) and RR 1.65, (95% CI 1.06 to 2.57) respectively.. Alitretinoin gel is effective in treating cutaneous KS, PLD is effective treatment for advanced KS and radiotherapy appears effective in treating cutaneous lesions. Apart from the trial of radiotherapy no trials applicable to developing settings were identified.

Topics: Alitretinoin; Antineoplastic Agents; Doxorubicin; HIV Infections; Humans; Liposomes; Randomized Controlled Trials as Topic; Sarcoma, Kaposi; Skin Neoplasms; Tretinoin

To evaluate the safety, dose tolerance, and anti-tumor effects of 9-cis-retinoic acid in the treatment of Kaposi sarcoma (KS) related to acquired immunodeficiency syndrome (AIDS).. Phase 2, open-label clinical trial of oral doses of 9-cis-retinoic acid increasing in 40-mg increments every 2 weeks from 60 mg/m(2) per day to a maximum of 140 mg/m( 2) per day.. Five hospital or health maintenance organization outpatient clinics.. Fifty-seven adult male patients with human immunodeficiency virus and biopsy-proven KS.. Safety was evaluated by adverse events, physical examination, laboratory test abnormalities, treatment-limiting toxic effects, and reasons for early withdrawal. Response (>/=50% improvement) was evaluated by an overall KS response and by the area and height from 6 index lesions selected at baseline.. Patients tolerated 60 and 100 mg/m(2) per day. Most patients found 140 mg/m(2) per day intolerable owing to headache. Common treatment-related adverse events were headache, xerosis, rash, alopecia, and hyperlipemia. The patient response rate for the overall KS disease was 19% (11/57), including 1 patient with clinically complete response. The response rate assessed by measuring 6 index lesions during treatment was 39% (22/57). Sixteen responding patients (73%) were refractory to at least 1 previous anti-KS therapy. Patients with CD4( +) counts of 150 cells/ micro L or lower were as likely to respond as patients with counts of higher than 150 cells/ micro L. The median time to response was 8.5 weeks (range, 4.0-21.1 weeks). The median duration of treatment was 15.1 weeks (range, 0.14 to >/=62 weeks).. 9-cis-retinoic acid capsules have moderate activity and provide durable responses, but substantial toxic effects at higher doses limit its suitability as an anti-KS therapy.

Topics: Acquired Immunodeficiency Syndrome; Adolescent; Adult; Alitretinoin; Antineoplastic Agents; Biopsy, Needle; Capsules; Dose-Response Relationship, Drug; Drug Administration Schedule; Follow-Up Studies; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Risk Assessment; Sarcoma, Kaposi; Single-Blind Method; Skin Neoplasms; Survival Rate; Treatment Outcome; Tretinoin

This randomized, double-blind and vehicle-controlled phase III study was conducted to evaluate the efficacy and safety of alitretinoin gel 0.1% for the topical treatment of the cutaneous lesions of AIDS-related Kaposi's sarcoma (KS).. Patients received treatment with alitretinoin gel (n = 62) or vehicle gel (n = 72) twice daily for 12 weeks. The primary efficacy endpoint was the cutaneous KS tumor response rate according to AIDS Clinical Trials Group (ACTG) objective criteria applied to topical therapy, with the patient as the unit of analysis.. Treatment of patients with alitretinoin gel resulted in a significant antitumor effect. The overall patient response rate (complete plus partial response) was 37% (23 of 62) for the alitretinoin-treated patients and 7% (5 of 72) for the vehicle-treated patients (p = 0.00003). The difference in response rates for the 2 treatment groups remained significant even after taking into consideration numerous variables, including age (p = 0.00001), Eastern Cooperative Oncology Group (ECOG) status (p = 0.00002), CD4+ cell count (p = 0.00002), history of opportunistic infection (p = 0.00002), aggregate area of indicator lesions (p = 0.00005), number of raised indicator lesions (p = 0.00002), prior therapy for KS (p = 0.00003), and number of drugs (p = 0.00002) used in concomitant antiretroviral therapy. Generally, treatment with alitretinoin gel was well tolerated. The overall incidence of adverse events was similar for the 2 treatment groups. Adverse events related to treatment with alitretinoin gel tended to be mild to moderate in severity and limited to the site of application. The most frequent adverse event occurring at the application site following alitretinoin gel treatment was irritation coded as rash (32%).. The results of this study provide convincing evidence of the superiority of alitretinoin gel over vehicle gel for the treatment of the cutaneous lesions of AIDS-related KS.

Topics: Administration, Topical; Adult; Alitretinoin; Antineoplastic Agents; Double-Blind Method; Drug Administration Schedule; Female; Gels; Herpesvirus 8, Human; Humans; Male; Palliative Care; Pharmaceutical Vehicles; Sarcoma, Kaposi; Skin Neoplasms; Treatment Outcome; Tretinoin

To evaluate the efficacy and safety of topical alitretinoin gel (9-cis-retinoic acid [LGD1057], Panretin gel; Ligand Pharmaceuticals, Inc, San Diego, Calif) in cutaneous Kaposi sarcoma (KS).. Open-label, within-patient, controlled, dose-escalating phase 1 and 2 clinical trials. In all patients, 1 or more cutaneous KS lesions were treated with alitretinoin gel, and at least 2 other lesions served as untreated controls for up to 16 weeks. Alitretinoin (0.05% or 0.1% gel) was applied twice daily for the first 2 weeks and up to 4 times daily thereafter, if tolerated.. Nine academic clinical centers.. One hundred fifteen patients with biopsy-proven acquired immunodeficiency syndrome (AIDS)-related KS.. AIDS Clinical Trials Group response criteria.. Statistically significant clinical responses were observed in 31 (27%) of 115 patients for the group of treated index lesions compared with 13 (11%) for the group of untreated control lesions (P<.001). Responses occurred with low CD4(+) lymphocyte counts (<200 cells/microL) and in some patients with refractory response to previous systemic anti-KS therapy. The incidence of disease progression was significantly lower for treated index lesions compared with untreated control lesions (39/115 [34%] vs 53/115 [46%]; P =.02). Alitretinoin gel generally was well tolerated, with 90% of treatment-related adverse events confined to the application site and only mild or moderate in severity.. Alitretinoin gel has significant antitumor activity as a topical treatment for AIDS-related KS lesions, substantially reduces the incidence of disease progression in treated lesions, and is generally well tolerated.

Topics: Administration, Cutaneous; Adult; AIDS-Related Opportunistic Infections; Alitretinoin; Antineoplastic Agents; Dose-Response Relationship, Drug; Drug Administration Schedule; Gels; Humans; Male; Middle Aged; Sarcoma, Kaposi; Skin Neoplasms; Treatment Outcome; Tretinoin; United States

Compound

Topics: Humans; Inflammation; Ligands; Retinoid X Receptors; Skin Neoplasms; Tetrahydronaphthalenes; Tretinoin; Triglycerides

Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common subtypes of cutaneous T-cell lymphoma (CTCL). There is currently no cure for CTCL, and treatment is aimed at limiting disease progression. This study evaluated the efficacy and tolerability of alitretinoin in CTCL management.. A retrospective, multicenter study was conducted on CTCL patients treated with alitretinoin as a primary agent or in combination with standard therapies.. Forty-eight patients with MF (n = 40) and SS (n = 8) with a median age of 59.7 years (±14.3) were eligible for study inclusion. Treatment response data were evaluated in 40 patients and safety in 42 patients. 40.0% of the patients had early-stage, 43.8% had advanced-stage CTCL, and in 16.7% of patients there was insufficient information for staging. 40.0% (16/40) of the patients achieved a complete or partial response, whereas 47.5% (19/40) achieved stable disease, 12.5% (5/40) had progressive disease, and there were no cases of disease relapses in responders. Both early and advanced stages of CTCL were responsive to alitretinoin as a primary or combined modality. Alitretinoin was well tolerated, and 64.3% (27/42) of patients did not report any side effects. The most commonly observed side effect was hypertriglyceridemia.. This retrospective analysis supports the efficacy and safety of alitretinoin in clearing skin disease and preventing disease progression in CTCL as a monotherapy or in combination with standard therapies.

Topics: Adult; Aged; Aged, 80 and over; Alitretinoin; Antineoplastic Agents; Canada; Combined Modality Therapy; Female; Humans; Male; Middle Aged; Mycosis Fungoides; Retrospective Studies; Sezary Syndrome; Skin Neoplasms; Treatment Outcome; Young Adult

In this survey, we analyzed data from patients suffering from the most common cutaneous T-cell lymphomas (CTCLs) subtypes mycosis fungoides (MF) and Sézary syndrome (SS), treated with the retinoid alitretinoin during a 7-year period at our outpatient department between 2015 and 2020.. We analyzed patient medical records including TNMB stage, side effects under therapy with alitretinoin, time to next treatment (TTNT), and previous photo documentation.. A total of 35 patients with MF (n = 28) and SS (n = 7) were included in the study, of whom 69% were male and 31% were female. The mean age of onset was 56 ± 15 years in MF and 65.4 ± 10.8 years in SS with 51.4% having early stage (IA-IIA) and 48.6% having advanced stage (IIB-IVA) CTCL. Of these patients 37.2% responded to alitretinoin, 28.6% had a stable course, and 34.3% experienced progression. Alitretinoin was administered as a monotherapy (25.7%) or combined with five concomitant therapies (74.2%), most frequently with ECP (31.4%) and PUVA (11.4%). 63% did not report any side effects, most often hypertriglyceridemia (20%) was described.. Considering that nearly two thirds of the CTCL patients treated with alitretinoin showed a response or stable disease, together with a low number of side effects and low cost compared to bexarotene, alitretinoin may be a potential alternative in the treatment of less advanced CTCLs. This survey represents the largest number of recorded therapies with the retinoid alitretinoin in CTCLs in a European patient collective.

Topics: Adult; Aged; Alitretinoin; Antineoplastic Agents; Bexarotene; Combined Modality Therapy; Disease Progression; Female; Humans; Lymphoma, T-Cell, Cutaneous; Male; Middle Aged; Mycosis Fungoides; PUVA Therapy; Sezary Syndrome; Skin Neoplasms

The vitamin A derivative 9-cis-retinoic acid (9-cis-RA) has been used for the treatment and prevention of cutaneous T-cell lymphoma (CTCL). However, the precise mechanism by which 9-cis-RA treatment ameliorates CTCL remains elusive. Our research shows that 9-cis-RA inhibits proliferation and induces apoptosis in CTCL cells in a dose-dependent and time-dependent manner. 9-Cis-RA also induced G0/G1 cell cycle arrest by downregulation of cyclin D1. We confirmed that 9-cis-RA significantly decreased phosphorylation of JAK1, STAT3, and STAT5 and downregulated Bcl-xL and cyclin D1, indicating that 9-cis-RA inhibited the activation of JAK/STAT signaling. Meanwhile, 9-cis-RA also activated classical RA-mediated transcription by retinoic acid receptors (RAR) and/or retinoid X receptors (RXR) in a CTCL cell line. Thus, 9-cis-RA may be effective for chemotherapy and may prevent human CTCL by inhibiting proliferation and inducing apoptosis by inhibition of the JAK/STAT pathway and activation of the RAR/RXR pathway.

Topics: Alitretinoin; Antineoplastic Agents; Apoptosis; Cell Proliferation; Down-Regulation; G1 Phase Cell Cycle Checkpoints; Humans; Janus Kinases; Lymphoma, T-Cell, Cutaneous; Nitriles; Pyrazoles; Pyrimidines; Receptors, Retinoic Acid; Resting Phase, Cell Cycle; RNA, Messenger; Skin Neoplasms; STAT Transcription Factors

Topics: Alitretinoin; Antineoplastic Agents; Cell Transformation, Neoplastic; Humans; Ki-1 Antigen; Male; Middle Aged; Mycosis Fungoides; Skin Neoplasms; Tretinoin

Topics: Alitretinoin; Antineoplastic Agents; Female; Foot Dermatoses; Hand Dermatoses; Humans; Middle Aged; Mycosis Fungoides; Skin Neoplasms; Treatment Outcome; Tretinoin

Topics: Aged; Alitretinoin; Antineoplastic Agents; Female; Forearm; Humans; Indoles; Keratoacanthoma; Melanoma; Proto-Oncogene Proteins B-raf; Retinoids; Skin Neoplasms; Sulfonamides; Tretinoin; Vemurafenib

Aldehyde dehydrogenase 1A1 (ALDH1A1), an enzyme that catalyses the conversion of lipid aldehydes to lipid carboxylic acids, plays pleiotropic roles in UV-radiation resistance, melanogenesis and stem cell maintenance. In this study, a combination of RNAi and pharmacologic approaches were used to determine which ALDH1A1 substrates and products regulate melanogenesis. Initial studies revealed that neither the UV-induced lipid aldehyde 4-hydroxy-2-nonenal nor the ALDH1A1 product all-trans retinoic acid appreciably induced melanogenesis. In contrast, both the ALDH1A1 substrate 9-cis retinal and its corresponding product 9-cis retinoic acid potently induced the accumulation of MITF mRNA, Tyrosinase mRNA and melanin. ALDH1A1 depletion inhibited the ability of 9-cis retinal but not 9-cis retinoic acid to stimulate melanogenesis, indicating that ALDH1A1 regulates melanogenesis by catalysing the conversion of 9-cis retinal to 9-cis retinoic acid. The addition of potent ALDH1A inhibitors (cyanamide or Angeli's salt) suppressed Tyrosinase and MITF mRNA accumulation in vitro and also melanin accumulation in skin equivalents, suggesting that 9-cis retinoids regulate melanogenesis in the intact epidermis. Taken together, these studies not only identify cyanamide as a potential novel treatment for hyperpigmentary disorders, but also identify 9-cis retinoic acid as a pigment stimulatory agent that may have clinical utility in the treatment of hypopigmentary disorders, such as vitiligo.

Topics: Aldehyde Dehydrogenase; Aldehyde Dehydrogenase 1 Family; Alitretinoin; Cell Line, Tumor; Cells, Cultured; Cyanamide; Humans; Melanins; Melanocytes; Melanoma; Microphthalmia-Associated Transcription Factor; Monophenol Monooxygenase; Retinal Dehydrogenase; Skin; Skin Neoplasms; Skin Pigmentation; Tretinoin

Topics: Aged; Alitretinoin; Antineoplastic Agents; Hand; Humans; Male; Pagetoid Reticulosis; Skin Neoplasms; Treatment Outcome; Tretinoin

Topics: Alitretinoin; Antineoplastic Agents; Humans; Male; Middle Aged; Mycosis Fungoides; Skin Neoplasms; Tretinoin

Topics: Aged; Alitretinoin; Antineoplastic Agents; Humans; Keratoderma, Palmoplantar; Male; Mycosis Fungoides; Photopheresis; Sezary Syndrome; Skin Neoplasms; Treatment Outcome; Tretinoin

Topics: Aged; Alitretinoin; Antineoplastic Agents; Gels; Humans; Male; Sarcoma, Kaposi; Skin Neoplasms; Treatment Failure; Tretinoin

Topics: Administration, Topical; Aged; Aged, 80 and over; Alitretinoin; Antineoplastic Agents; Female; Gels; Humans; Sarcoma, Kaposi; Skin Neoplasms; Tretinoin

Topics: Alitretinoin; Antineoplastic Agents; Gels; Humans; Lymphoma, T-Cell, Cutaneous; Male; Middle Aged; Skin Neoplasms; Tretinoin

We recently demonstrated that the constitutive expression of cyclooxygenase (COX)-2 protein and prostaglandin E(2) (PGE(2)) biosynthesis were significantly enhanced in human skin epidermal cancer cells and that cancer cell growth was effectively inhibited by the suppression of COX-2 expression by transfection with COX-2 antisense oligonucleotide. The purpose of this study was to search for agents which suppress COX-2 expression and examine their effects on cell growth. Since retinoids and antioxidants have been used for chemoprevention of cancers in several tissues, the effects of these agents on COX-2 expression and PGE(2) biosynthesis in skin squamous carcinoma cells were investigated. Treatment with a retinoid (9-cis-retinoic acid (9-cis-RA)) or an antioxidant (pyrrolidinedithiocarbamate (PDTC)) suppressed COX-2 expression and PGE(2) biosynthesis in a concentration-dependent manner. Cell growth was significantly inhibited by 9-cis-RA and PDTC. These results suggest that 9-cis-RA and PDTC may be useful in preventing skin cancer growth and that COX-2 is involved in their protective effects on skin carcinogenesis.

Topics: Acetylcysteine; Alitretinoin; Antineoplastic Agents; Antioxidants; Blotting, Western; Carcinoma, Squamous Cell; Cell Division; Cell Line; Cyclooxygenase 2; Dinoprostone; Dose-Response Relationship, Drug; Free Radical Scavengers; Humans; Isoenzymes; Keratinocytes; Membrane Proteins; Oligonucleotides, Antisense; Prostaglandin-Endoperoxide Synthases; Pyrrolidines; Retinoids; Skin Neoplasms; Thiocarbamates; Time Factors; Transfection; Tretinoin; Tumor Cells, Cultured

Topics: Administration, Cutaneous; AIDS-Related Opportunistic Infections; Alitretinoin; Anti-HIV Agents; Dermatologic Agents; Drug Administration Schedule; Humans; Sarcoma, Kaposi; Skin Neoplasms; Treatment Outcome; Tretinoin

We recently demonstrated that conformationally defined 6-s-trans-retinoic acid (RA) analogs were effective in the prevention of skin papillomas (Vaezi et al. J. Med. Chem. 1994, 37, 4499-4507) and selective agonists for nuclear receptor binding and activation (Alam et al. J. Med. Chem. 1995, 38, 2302-2310). In order to probe important structure-activity relationships, we evaluated a homologous series of four 6-s-trans-retinoids that are 8-(2'-cyclohexen-1'-ylidene)-3,7-dimethyl-2,4,6-octatrienoic acids with different substituents at 2' (R2) and 3' (R1) positions on the cyclohexene ring. UAB1 (R1 = R2 = H), UAB4 (R1 = R2 = Me), UAB7 (R1 = Me, R2 = iPr), and UAB8 (R1 = Et, R2 = iPr) contain alkyl R groups that mimic, to different extents, portions of the trimethylcyclohexenyl ring of RA. Both 9Z- and all-E-isomers of these retinoids were evaluated in binding assays for cellular retinoic acid-binding proteins (CRABP-I and CRABP-II), a nuclear retinoic acid receptor (RAR alpha), and a nuclear retinoid X receptor (RXR alpha). The all-E-isomers of UAB retinoids bound tightly to CRABPs and RAR alpha, the binding affinity of the all-E-isomer increased systematically from UAB1 to UAB8, and binding for the latter was comparable to that of all-E-RA. In contrast to RA, the (9Z)-UAB retinoids were at least 200-fold less active than the all-E-isomers in binding to RAR alpha. The (9Z)-UAB isomers exhibited increasingly stronger binding to RXR alpha, and (9Z)-UAB8 was nearly as effective as (9Z)-RA in binding affinity. The retinoids were also evaluated in gene expression assays mediated by RAR alpha and RXR alpha homodimers or RAR alpha/RXR alpha heterodimers. Consistent with the binding affinities, the (all-E)-UAB retinoids activated gene transciption mediated by RAR alpha homodimers or RAR alpha/RXR alpha heterodimers, while the (9Z)-UAB isomers activated only the RXR alpha homodimer-mediated transcription. The all-E- and 9Z-isomers of the UAB retinoids were further evaluated for their capacity to prevent the induction of mouse skin papillomas. When compared to RA, only the (all-E)-UAB retinoids containing bulky R1 and R2 groups were effective in this chemoprevention assay. (9Z)-RA displayed equal capacity as RA to prevent papillomas, while the 9Z-isomers of the UAB retinoids were much less effective. Taken together, these studies demonstrate that the cyclohexenyl ring substituents of 6-s-trans-UAB retinoids are important for their biological activities and that the ch

Topics: Animals; Anticarcinogenic Agents; Cell Nucleus; Mice; Models, Molecular; Molecular Conformation; Molecular Structure; Papilloma; Receptors, Retinoic Acid; Retinoid X Receptors; Retinoids; Skin Neoplasms; Stereoisomerism; Structure-Activity Relationship; Thermodynamics; Transcription Factors; Transcription, Genetic