Yanto Lunardi-Iskandar

The effects of preparations of human chorionic gonadotropin on AIDS- related Kaposi's sarcoma

BACKGROUND Kaposis sarcoma is the most common cancer in patients with the acquired immunodeficiency syndrome (AIDS). Recently, certain preparations of human chorionic gonadotropin (hCG) have been shown to inhibit the growth of Kaposis sarcoma cell lines in vitro and in immunodeficient mice. METHODS After in vitro evaluation of four commercially available hCG preparations, the most active product was evaluated in 36 patients with AIDS-related Kaposis sarcoma. In a phase 1-2 trial, 24 patients received intralesional injections of hCG three times a week for two weeks at doses of 250, 500, 1000, or 2000 IU (6 patients each). In each patient three nodular lesions were injected, two with the drug and one with diluent alone. In a double-blind trial, 12 additional patients were randomly assigned to receive intralesional injections of 2000 IU of hCG or diluent alone (6 patients each; two lesions per patient). At the conclusion of therapy, the lesions were measured, their gross appearance assessed, and biopsy specimens evaluated. RESULTS A.P.L. (Wyeth-Ayerst), which had the most in vitro activity against Kaposis sarcoma cell lines, was selected for the clinical investigation. Treatment with A.P.L. was well tolerated at all doses. In the cohorts given 250, 500, 1000, and 2000 IU, 1, 5, 5, and 10 of the 12 injected lesions responded, respectively (P=0.03 for trend). Complete tumor regression was observed in one lesion each at the 250-IU and 500-IU doses, in two lesions given the 1000-IU dose, and in five lesions given the 2000-IU dose. In the double-blind study, none of the 12 lesions in the six patients injected with diluent had responses, as compared with 10 of the 12 lesions in the six patients injected with hCG (P=0.015). Microscopical evidence of apoptosis was observed only in hCG-treated lesions. The percentage of cells that died increased in a dose-dependent manner (P<0.001). Serum levels of follicle-stimulating hormone (P=0.002) and luteinizing hormone (P=0.001) declined after the last injection of hCG, but there was no effect on these hormones in the diluent-treated patients. CONCLUSIONS The intralesional injection of hCG induces the regression of AIDS-related Kaposis sarcoma lesions in a dose-dependent manner. The response of these tumors appears to be mediated by the induction of apoptosis.

Effects of interleukin-1 and interleukin-1 receptor antagonist in AIDS-Kaposi's sarcoma

Kaposis sarcoma (KS) is the most common tumor seen in patients with HIV-1 infection. HIV-1 may induce KS directly through viral protein(s) or indirectly through regulation of cytokines such as IL-1 and IL-6. We have shown that AIDS-KS spindle cells express IL-1 beta and that IL-1ra inhibits KS-spindle cell growth. IL-1ra had little effect on human umbilical vein endothelial cells (HUVEC), human aortic smooth muscle cells (HASM), and human foreskin fibroblast (NN41). These findings support an autocrine activity for IL-1. Furthermore, exogenous IL-1 can enhance AIDS-KS cell growth, and this effect is completely blocked by IL-1ra. As expected, IL-1ra also blocks IL-1 mediated upregulation of IL-6 and bFGF, both of which are autocrine growth factors for KS. IL-1ra is thus a potential candidate for the treatment of AIDS-associated KS.

B cell lymphoma in HIV transgenic mice.

BackgroundHuman Immunodeficiency Virus Type I (HIV-1) infection is associated with a high incidence of B-cell lymphomas. The role of HIV in these lymphomas is unclear and currently there are no valid in vivo models for better understanding HIV-related lymphomagenesis. Transgenic (Tg) 26 mice have a 7.4-kb pNL4-3 HIV-1 provirus lacking a 3.1-kb sequence encompassing parts of the gag-pol region. Approximately 15% of these HIV Tg mice spontaneously develop lymphoma with hallmark pre-diagnostic markers including skin lesions, diffuse lymphadenopathy and an increase in pro-inflammatory serum cytokines. Here we describe the phenotypic and molecular characteristics of the B cell leukemia/lymphoma in the Tg mice.ResultsThe transformed B cell population consists of CD19+pre-BCR+CD127+CD43+CD93+ precursor B cells. The tumor cells are clonal and characterized by an increased expression of several cellular oncogenes. Expression of B cell-stimulatory cytokines IL-1β, IL-6, IL-10, IL-12p40, IL-13 and TNFα and HIV proteins p17, gp120 and nef were elevated in the Tg mice with lymphoma.ConclusionsIncreased expression of HIV proteins and the B-cell stimulatory factors is consistent with the interpretation that one or more of these factors play a role in lymphoma development. The lymphomas share many similarities with those occurring in HIV/AIDS+ patients and may provide a valuable model for understanding AIDS-related lymphomagenesis and elucidating the role played by HIV-1.

Abstract 4367: IP6: A potential novel therapy for cancer stem cells

Background and Aims: We recently discovered that inositol hexaphosphate (IP6), a new anticancer agent, killed malignant cancer stem cells (CSC) such as: CD133+, CD44+ and CD24+ cells via apoptotic pathways, but did not kill normal epithelial cells, fibroblasts, lymphocytes and macrophages. The effects of IP6 on malignant CSC have not been known. To clarify the molecular mechanism of IP6 destruction of CSC cells, we studied its effects in several CSC from malignant KS-Y1, B-NHL, prostate cancer (PCA) and breast cancer (BCA) cell lines. Methods and Results: CSC were isolated from KSY-1, B-NHL/HIV Tg26 mice, PCA and BCA cancer cell lines using magnetic beads conjugated with MoAbs and analyzed by flow cytometry for CD133, CD44 and CD24 cells. CSC cells were cultured using liquid and semisolid techniques for tumorigenesis assay and were treated with IP6 at doses of 100, 300 and 500 µg/ml, untreated (PBS) and control treatment with 10-100 µg/ml of Taxol. Cell viability was determined by trypan blue at 1 hr-24 hrs. FACS analyses were performed for apoptotic activities by detection of death molecules such as Annexin V-FITC and PI-CD95, and apoptosis assessed by 3D confocal microscopy. Significant killing of malignant CSC with IP6 in a dose-dependent manner were shown ex vivo in proliferation/differentiation tumorigenesis assay, in quantitative/qualitative FACS analyses and 3D confocal microscopy. In contrast, Taxol molecule with doses 10-100 µg/ml did not kill the CSC. Since it is known that CSC are resistant to Taxol treatment and radiation therapy, and IP6 significanly decreased proliferation and induced apoptosis in malignant and metastatic CSC, the results from our experiments suggest that IP6 may be an excellent new drug for treatment of CSC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4367. doi:10.1158/1538-7445.AM2011-4367