pyrimidinones and Sarcoma--Kaposi

Given that HIV-protease inhibitors (HIV-PIs) are substrates/inhibitors of the multidrug transporter ABCB1, can induce ABCB1 expression, and are used in combination with doxorubicin for AIDS-Kaposi's Sarcoma (KS) treatment, the role that ABCB1 plays in mediating multidrug resistance (MDR) in a fully transformed KS cell line (SLK) was explored.. The KS cells were exposed to both acute and chronic treatments of physiological concentrations of different HIV-PIs (indinavir, nelfinavir, atazanavir, ritonavir, or lopinavir), alone or together with doxorubicin. The ABCB1 mRNA and protein expression levels were then assessed by qRT-PCR and western blotting, flow cytometry, and immunofluorescence.. Chronic treatment of SLK cells with one of the five HIV-PIs alone or together resulted in increased resistance to doxorubicin. Co-treatment with one of the HIV-PIs in combination with doxorubicin resulted in a synergistic increase in resistance to doxorubicin, and the degree of resistance was found to correlate with the expression of ABCB1. The SLK cells were also revealed to be cross-resistant to the structurally unrelated drug paclitaxel.. These studies suggest that ABCB1 is primarily responsible for mediating MDR in SLK cells selected with either HIV-PIs alone or in combination with doxorubicin. Therefore, the roles that ABCB1 and drug cocktails play in mediating MDR in KS in vivo should be evaluated.

Topics: Antibiotics, Antineoplastic; Atazanavir Sulfate; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Blotting, Western; Cell Line, Tumor; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Synergism; Flow Cytometry; Fluorescent Antibody Technique; Gene Expression Regulation, Neoplastic; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lopinavir; Nelfinavir; Oligopeptides; Pyridines; Pyrimidinones; Reverse Transcriptase Polymerase Chain Reaction; Ritonavir; Sarcoma, Kaposi; Treatment Outcome

The coadministration of protease inhibitors with anticancer drugs in the management of human immunodeficiency virus-related malignancies can cause potential drug-drug interactions. The effect of lopinavir/ritonavir (LPV/RTV) on the pharmacokinetics of irinotecan (CPT11) has been investigated in seven patients with Kaposi's sarcoma. Coadministration of LPV/RTV reduces the clearance of CPT11 by 47% (11.3+/-3.5 vs 21.3+/-6.3 l/h/m(2), P=0.0008). This effect was associated with an 81% reduction (P=0.02) of the AUC (area under the curve) of the oxidized metabolite APC (7-ethyl-10-[4-N-(5-aminopentanoic-acid)-1-piperidino]-carbonyloxycamptothecin). The LPV/RTV treatment also inhibited the formation of SN38 glucuronide (SN38G), as shown by the 36% decrease in the SN38G/SN38 AUCs ratio (5.9+/-1.6 vs 9.2+/-2.6, P=0.002) consistent with UGT1A1 inhibition by LPV/RTV. This dual effect resulted in increased availability of CPT11 for SN38 conversion and reduced inactivation on SN38, leading to a 204% increase (P=0.0001) in SN38 AUC in the presence of LPV/RTV. The clinical consequences of these substantial pharmacokinetic changes should be investigated.

Topics: Adenine; Adult; Aged; Anti-HIV Agents; Antineoplastic Agents, Phytogenic; Antiretroviral Therapy, Highly Active; Area Under Curve; Camptothecin; Drug Therapy, Combination; HIV Infections; Humans; Irinotecan; Lamivudine; Lopinavir; Male; Middle Aged; Organophosphonates; Pyrimidinones; Ritonavir; Sarcoma, Kaposi; Tenofovir; White People

Topics: Administration, Oral; Adult; Antineoplastic Agents, Phytogenic; Antiretroviral Therapy, Highly Active; Camptothecin; Drug Interactions; HIV Infections; HIV Protease Inhibitors; Humans; Irinotecan; Lopinavir; Male; Pyrimidinones; Ritonavir; Sarcoma, Kaposi

Topics: HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Pleural Effusion; Pyrimidinones; Sarcoma, Kaposi