tretinoin and Acquired-Immunodeficiency-Syndrome

Kaposi's sarcoma (KS) is an opportunistic tumor that develops with increased frequency (100,000-fold) after HIV infection. KS causes significant morbidity from mucocutaneous involvement and mortality from complications of visceral sites of disease such as the lungs, gastrointestinal tract, and the liver. Progressive unraveling of the KS pathogenesis has lead to the development of novel therapeutic approaches. Newest therapies are first evaluated in patients with limited tumor burden. These include: 1) inhibitors of angiogenesis such as vascular endothelial growth factor signaling inhibitor (SU 5416), and several other inhibitors of angiogenesis such as the dipeptide IM 862, TNP-470, Col-3, and thalidomide; 2) topical and systemic retinoids; 3) antiviral agents specific for Kaposi's sarcoma herpesvirus and human herpesvirus-8, or HIV; and 4) pregnancy-related factors. Patients with advanced disease such as widespread mucocutaneous disease, lymphedema, and visceral disease are treated most effectively with cytotoxic agents. The most active agents include liposomal anthracyclines, paclitaxel, vinca alkaloids, and bleomycin. The combination of liposomal anthracyclines and paclitaxel, with and without the most promising biologicals, should now be studied to further reduce the toxicity, and enhance the antitumor effects. Furthermore, identification of risk factors for KS should serve to explore prophylactic therapies.

Topics: Acquired Immunodeficiency Syndrome; AIDS-Related Opportunistic Infections; Angiostatins; Antineoplastic Agents; Antiviral Agents; Chorionic Gonadotropin; Collagen; Drug Therapy, Combination; Endostatins; Herpesvirus 8, Human; HIV-1; Peptide Fragments; Plasminogen; Sarcoma, Kaposi; Tissue Inhibitor of Metalloproteinases; Tretinoin

Kaposi's sarcoma (KS) is the most common tumor associated with AIDS. A growing number of patients with this tumor are presenting at later stages of HIV with more rapidly progressive, extensive, or symptomatic KS or with tumors involving visceral organs. Chemotherapy treatment is effective in inducing tumor regression, reducing edema, and ameliorating symptoms caused by these tumors. Side effects and toxicities from these agents, however, can be quite pronounced, especially in patients with advanced AIDS Antiretroviral therapy, prophylaxis for opportunistic infections, and the use of hematopoietic growth factors should be routinely included in the management of these patients. Newer chemotherapeutic agents and combination regimens may be more effective or less toxic than previously evaluated regimens.

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Antineoplastic Agents; Drug Therapy, Combination; Hematopoietic Cell Growth Factors; Humans; Liposomes; Neoplasm Staging; Phototherapy; Sarcoma, Kaposi; Tretinoin

Dermal dendrocytes represent a population of resident cells of the dermis identified recently by virtue of the immunohistochemical expression of the coagulation factor XIIIa (fXIIIa). These dendritic cells of bone-marrow origin bear particular histoenzymatic and immunohistochemical features, some of which are shared with antigen-presenting cells; however, they are clearly distinct from epidermal Langerhans cells. Dermal dendrocytes could act as macrophages, antigen-presenting cells or participate in the homeostasis of macromolecules of the dermis. These cells give rise to some cutaneous tumours and seem involved in inflammatory dermatoses where they act by means of cytokine production; they could even represent targets of HIV infection. Future functional studies will hopefully lead to a better understanding of their precise role in normal and diseased skin, which remains presently partly speculative.

Topics: Acquired Immunodeficiency Syndrome; Cytokines; Dermatitis; Granuloma; Histiocytoma, Benign Fibrous; HLA-DR Antigens; Humans; Sarcoma, Kaposi; Skin; Skin Neoplasms; Skin Physiological Phenomena; Transglutaminases; Tretinoin; Ultraviolet Rays; Vasculitis, Leukocytoclastic, Cutaneous

An approach to anti-AIDS chemotherapy is presented from the point of view of treating seropositive individuals by eliminating the infected dendritic cells that are the in vivo target of HIV-1. Special attention is given to the treatment of Langerhans (dendritic) cells in the skin and epithelia that are infected in vivo by HIV and are involved in the development of the symptoms leading to AIDS and ARC. Since HIV is released through the cervical and vaginal epithelia in seropositive women, it is suggested that combined local treatment of vaginal epithelium with steroids that inactivate dendritic cells and azidothymidine (AZT) that inhibits HIV-1 replication might prevent virus dissemination. Abrogation of HIV-1 transmission will help to prevent its spread throughout the heterosexual population. Thus a new rationale for anti-AIDS treatment is presented, namely selective elimination of HIV-1 infected dendritic cells in the skin and epithelia of infected individuals before the appearance of ARC or AIDS. Subsequent restoration of dendritic cells in HIV-1-infected persons (and in AIDS patients) by means of orally administered retinoids in combination with an antiviral drug might be a useful approach to prevent or delay AIDS.

Topics: Acquired Immunodeficiency Syndrome; Administration, Topical; Adrenal Cortex Hormones; AIDS-Related Complex; Combined Modality Therapy; Dendritic Cells; Drug Therapy, Combination; Female; HIV Seropositivity; HIV-1; Humans; Meta-Analysis as Topic; Tretinoin; Ultraviolet Therapy; Zidovudine

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

A multicenter trial was conducted to determine the efficacy and toxicity of escalating dosages of liposomal tretinoin (all-trans-retinoic acid) administered once or three times weekly in patients with acquired immunodeficiency syndrome (AIDS)-associated Kaposi sarcoma.. Seventy-six patients with acquired immunodeficiency syndrome (AIDS)-associated Kaposi sarcoma were randomized to receive the study drug either once (n = 30) or 3 times weekly (n = 46). The starting dosage was 60 mg/m(2), which was escalated to 90 mg/m(2) and then 120 mg/m(2) if the drug was well tolerated (

Topics: Acquired Immunodeficiency Syndrome; Adolescent; Adult; Aged; Antineoplastic Agents; Drug Carriers; Female; Gastrointestinal Diseases; Humans; Infusions, Intravenous; Liposomes; Male; Middle Aged; Quality of Life; Sarcoma, Kaposi; Treatment Outcome; Tretinoin

To assess the efficacy and safety of all-trans-retinoic acid (ATRA), a retinoid with antitumour activity that inhibits in vitro the growth of Kaposi's sarcoma cells, in patients with low-risk AIDS-associated Kaposi's sarcoma.. Non-randomized phase II study, using a group sequential procedure to determine whether the response rate to ATRA was above 10%.. Nine referral French centres.. Twenty HIV-seropositive men with CD4 cells > or = 200 x 10(6)/l, low-risk Kaposi's sarcoma [T0I0S0 according to the classification of AIDS Clinical Trials Group (ACTG)] not previously treated with systemic anti-Kaposi's sarcoma agents, and with at least four measurable lesions were included.. ATRA was given orally 45 mg/m2 daily for 12 weeks.. Tumour response evaluated according to ACTG criteria.. Nineteen patients were evaluated for response: partial response, stabilization and progression were found in eight (42%), seven (37%), and four (21%) patients, respectively. Gradual flattening and lightening of lesions was observed in responders after at least 2 months of ATRA. All patients with partial response at week 12 pursued ATRA for another 15+/-7 weeks. Further improvement was observed in six patients. Median duration of response was 332 days. Cheilitis, transient headaches and skin dryness were the main toxicities noted. No significant changes in HIV viral burden or serum interleukin-6 pathways were observed.. ATRA is well tolerated and effective enough in Kaposi's sarcoma patients to warrant further evaluation.

Topics: Acquired Immunodeficiency Syndrome; Administration, Oral; Adult; Antineoplastic Agents; Cytokines; Female; Follow-Up Studies; HIV-1; Humans; Male; Middle Aged; Sarcoma, Kaposi; Tretinoin; Viral Load

Administration of all-trans-retinoic acid (ATRA) on a continuous daily schedule results in a rapid and sustained decrease in plasma drug concentrations. This pharmacokinetic study was performed to determine if administration of ATRA on an intermittent schedule could overcome the rapid decrease in plasma drug concentration and provide repetitive periods of higher plasma drug exposure.. ATRA was administered on repetitive cycles of 7 consecutive days of drug followed by 7 days without drug. On the days of pharmacokinetic monitoring, following an overnight fast, a fixed single oral dose of 40 mg/m2 was administered and frequent plasma samples were obtained over 8 hours. Patients had pharmacokinetic studies performed on the first and seventh days of the first week, and on the first day of the third and eleventh weeks. ATRA was measured in plasma with a reverse-phase high-performance liquid chromatography (HPLC) assay.. Plasma exposure to ATRA as measured by the area under the plasma concentration-time curve (AUC) decreased significantly during the first week of drug administration, from a mean of 145 +/- 26 mumol/L.min on day 1 to 18 +/- 4 mumol/L.min by day 7. Plasma ATRA concentrations at the start of weeks 3 and 11 of this every-other-week schedule were equivalent to those achieved on day 1 of treatment, with mean AUCs of 177 +/- 39 and 128 +/- 30 mumol/L.min, respectively.. An intermittent schedule of ATRA administration results in repetitive periods of exposure to concentrations of ATRA normally only observed on the first day of treatment. Phase II trials to evaluate the role of intermittent schedules of administration for ATRA are planned.

Topics: Acquired Immunodeficiency Syndrome; Adult; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Tolerance; Half-Life; Humans; Leukemia, Promyelocytic, Acute; Middle Aged; Remission Induction; Sarcoma, Kaposi; Tretinoin; Up-Regulation

Retinoids have anti-tumor activity in several malignant and premalignant conditions. Since Kaposi's sarcoma is regulated by steroid hormones both in vivo and in vitro, we hypothesized that retinoids may have anti-tumor effects in AIDS-related Kaposi's sarcoma. Thus, 27 patients with mucocutaneous, non-visceral AIDS-related Kaposi's sarcoma were treated with all-trans retinoic acid (tRA). Poor tolerance was observed at the initial starting dose of 150 mg/m2, and thus subsequent patients were treated using a weekly dose escalation, starting with 45 mg/m2 (given daily, in subdivided doses), to the target dose of 150 mg/m2 (given daily in three subdivided doses). Nearly half (46%) of the patients had extensive mucocutaneous disease with over 25 lesions. No patient had received prior cytotoxic chemotherapy. Ten patients had CD4 lymphocytes of 200/mm3 or greater (strata I); and 17 had under 200/mm3 CD4 lymphocytes (strata II). The median of the average daily tRA dose administered was 150 mg (90 mg/m2; there was no significant difference in the dose tolerance between the two strata). Adverse effects consisted of transient mild to moderate headaches in 65% of patients, mild to moderate skin dryness and cheilitis in 61%, and nausea and vomiting in 31%. Hematologic toxicities included hypertriglyceridemia in 62%, anemia in 23%, and neutropenia in 23%. Partial response to therapy was observed in 4/24 (17%) evaluable patients, occurring after 12, 20, 24, and 28 weeks of therapy, and lasting 4-24 weeks. Three responders had baseline CD4 lymphocyte counts < 200/mm3. Three additional patients experienced reduction in measured indicator lesions of greater than 25% but less than 50%, and seven patients experienced disease stabilization of 16 weeks or greater. In evaluable patients, the median time to disease progression was 22 weeks and the overall median survival in all patients was 27.3 months. No significant changes in CD4 lymphocyte counts, p24 antigen, and beta 2 microglobulin were observed over time. However, a statistically significant increase was observed in soluble IL-2 receptor levels while on tRA (p = 0.037). We conclude that tRA has activity in patients with mucocutaneous AIDS-related Kaposi's sarcoma with acceptable toxicity. tRA has immunological effects without upregulation of HIV parameters. Additional studies in combinations or with more active retinoids are warranted.

Topics: Acquired Immunodeficiency Syndrome; Adult; Aged; Antineoplastic Agents; CD4 Lymphocyte Count; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Pilot Projects; Receptors, Interleukin-2; Sarcoma, Kaposi; Survival Analysis; Treatment Outcome; Tretinoin

Topics: Acquired Immunodeficiency Syndrome; Administration, Oral; Adult; HIV Seropositivity; Humans; Male; Middle Aged; Prospective Studies; Sarcoma, Kaposi; Skin Neoplasms; Tretinoin

Although the brain is an important target for the human immunodeficiency virus type 1 (HIV) and viral infection causes neuronal degeneration and dementia, the mechanisms responsible for HIV transcription in neuronal cells are largely unknown. We show here that retinoic acid (RA) stimulates HIV transcription in human neuronal SH-SY5Y cells. The steroid receptor coactivator 1 (SRC-1) enhances the transcriptional response to RA, and the viral protein Tat cooperates with RA and SRC-1 to induce a strong transactivation. These results suggest that retinoid receptors could play an important role as activators of viral gene expression in the human brain.

Topics: Acquired Immunodeficiency Syndrome; Brain; DNA-Binding Proteins; Gene Expression Regulation, Viral; Gene Products, tat; Histone Acetyltransferases; HIV-1; Humans; Nuclear Receptor Coactivator 1; Promoter Regions, Genetic; Receptors, Cytoplasmic and Nuclear; Receptors, Retinoic Acid; tat Gene Products, Human Immunodeficiency Virus; Terminal Repeat Sequences; Transcription Factors; Transcriptional Activation; Tretinoin; Tumor Cells, Cultured

Topics: Acquired Immunodeficiency Syndrome; Antineoplastic Agents; Dermatologic Agents; Drug Approval; Gels; Humans; Sarcoma, Kaposi; Tretinoin

Ligand Pharmaceuticals has received FDA approval for Panretin Gel (alitretinoin) for topical treatment of Kaposi's sarcoma. The company has also filed for approval in Europe and Canada. The gel is applied twice daily, and a 4- to 6-month course of therapy costs between $3,900 and $5,800. The main side effect is skin irritation; 7 percent of patients withdrew from trials because of skin toxicity. Panretin capsules have been tested in phase II clinical trials. Results of 2 trials with 402 patients were presented at the Retroviruses conference.

Topics: Acquired Immunodeficiency Syndrome; Administration, Topical; Antineoplastic Agents; Dermatologic Agents; Drug Approval; Gels; Humans; Sarcoma, Kaposi; Tretinoin; United States Food and Drug Administration

Topics: Acquired Immunodeficiency Syndrome; Adult; Antineoplastic Combined Chemotherapy Protocols; Humans; Interferon-alpha; Male; Sarcoma, Kaposi; Tretinoin

Retinoids, a group of natural and synthetic vitamin A analogues the receptors of which belong to the superfamily of steroid receptors, can exert profound effects on growth and/or differentiation of embryonic and neoplastic cells. Kaposi's sarcoma (KS), previously a rare multicentric neoplasm, has become epidemic with HIV infection, although the etiology of KS remains obscure. In the present study, the effects of two potent retinoids, all-trans-retinoic acid (RA) and 13-cis-RA, on the expression of retinoic acid receptor alpha and the growth of AIDS-related KS (AIDS-KS) cells were examined. The proliferation of AIDS-KS cells was significantly inhibited by RA and 13-cis-RA in a dose-dependent manner with 50% inhibitory concentration of 1.4 x 10(-10) M and 4.7 x 10(-9) M, respectively, which correlate with their potency. Growth inhibition was time dependent with maximal inhibition of 90% after 3 days of treatment with 10(-8) M RA. Growth inhibition by RA was further potentiated by forskolin (1 microM), an intracellular cyclic AMP-inducing agent. Moreover, RA treatment blocked the proliferative effect of oncostatin M and tumor necrosis factor alpha, two major KS autocrine growth factors. The effects of RA were accompanied by a dramatic increase in nuclear staining for retinoic acid receptor alpha and in the relative number of strongly positive retinoic acid receptor alpha nuclei. Finally, RA induced morphological changes as KS cells became more flattened, better spread, and more adhesive to the substrate. These results suggest that retinoids inhibit proliferation of AIDS-KS cells and further support their utility as therapeutic agents in AIDS-KS.

Topics: Acquired Immunodeficiency Syndrome; Animals; Cell Adhesion; Cell Division; Cell Nucleus; Cyclic AMP; Drug Synergism; Growth Inhibitors; Growth Substances; Humans; Kinetics; Mice; Oncostatin M; Peptides; Rats; Receptors, Retinoic Acid; Sarcoma, Kaposi; Tretinoin; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

Oral hairy leukoplakia was treated in six patients with (a) acyclovir (i.v. or p.o.), (b) 0.1% vitamin-A acid solution or (c) human beta-interferon-gel (10(5) I.E./g) in a total of 23 therapeutic courses. In 5/6 patients, acyclovir (7.5 mg/kg every 8 h i.v. or 5 x 400 mg p.o. over 5-10 days) led to partial (n = 1) or complete (n = 4) remission. After 1-6 months, however, the leukoplakia recurred in all cases. Vitamin-A acid solution (n = 3) led to remission in one and to improvement in the others. Human beta-interferon gel (n = 3) had no visible effect. The efficacy of acyclovir is further evidence of the concept that the Epstein-Barr virus is a major cause of oral hairy leukoplakia.

Topics: Acquired Immunodeficiency Syndrome; Acyclovir; Administration, Oral; AIDS-Related Complex; Drug Therapy, Combination; Humans; Infusions, Intravenous; Interferon Type I; Leukoplakia, Oral; Mouth Mucosa; Neoplasm Staging; Tretinoin