Use of antineoplastic agents in patients with cancer who have HIV/AIDS

Rudek, Michelle A.; Flexner, Charles; Ambinder, Richard F.

doi:10.1016/s1470-2045(11)70056-0

Cited by 124 publications

(121 citation statements)

References 98 publications

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“…In total, these studies support our proposition that NFV is an MRP4 substrate. On the basis of these studies and the potential for HIV patients to develop cancers that are typical of the non-HIV-infected population (Rudek et al, 2011;Deeken et al, 2012), we tested whether NFV would affect MTX cytotoxicity, because MTX is an MRP4 substrate (Chen et al, 2002) that is widely used in combination therapy to treat multiple cancers from acute lymphoblastic leukemia to breast cancer (Bonadonna et al, 1995;Pui and Evans, 2006). Like NFV, MTX inhibits PGE 2 -stimulated MRP4 ATP hydrolysis (Sauna et al, 2004), suggesting that these compounds occupy a similar or identical substrate binding site.…”

Section: Resultsmentioning

confidence: 99%

“…The incidence of non-AIDS-defining cancers (e.g., Hodgkin's lymphoma, lung, testicular germ-cell, breast) has increased significantly as patients with human immunodeficiency virus (HIV)/AIDS achieve longer life expectancy (Rudek et al, 2011;Deeken et al, 2012). These individuals are a therapeutic challenge because concurrent treatment with antineoplastic drugs and highly active antiretroviral therapy (HAART) might increase the potential for drug interactions (Rudek et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

“…These individuals are a therapeutic challenge because concurrent treatment with antineoplastic drugs and highly active antiretroviral therapy (HAART) might increase the potential for drug interactions (Rudek et al, 2011). The interactions between cancer chemotherapeutics and HAART drugs have the potential to increase the therapeutic benefit by increasing tumoricidal activity (De Clercq et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

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Human Immunodeficiency Virus Protease Inhibitors Interact with ATP Binding Cassette Transporter 4/Multidrug Resistance Protein 4: A Basis for Unanticipated Enhanced Cytotoxicity

et al. 2013

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Human immunodeficiency virus (HIV) pharmacotherapy, by combining different drug classes such as nucleoside analogs and HIV protease inhibitors (PIs), has increased HIV-patient life expectancy. Consequently, among these patients, an increase in non-HIVassociated cancers has produced a patient cohort requiring both HIV and cancer chemotherapy. We hypothesized that multidrug resistance protein 4/ATP binding cassette transporter 4 (MRP4/ABCC4), a widely expressed transporter of nucleosidebased antiviral medications as well as cancer therapeutics might interact with PIs. Among the PIs evaluated (nelfinavir, ritonavir, amprenavir, saquinavir, and indinavir), only nelfinavir both effectively stimulated MRP4 ATPase activity and inhibited substratestimulated ATPase activity. Saos2 and human embryonic kidney 293 cells engineered to overexpress MRP4 were then used to assess transport and cytotoxicity. MRP4 expression reduced intracellular accumulation of nelfinavir and consequently conferred survival advantage to nelfinavir cytotoxicity.Nelfinavir blocked Mrp4-mediated export, which is consistent with its ability to increase the sensitivity of MRP4-expressing cells to methotrexate. In contrast, targeted inactivation of Abcc4/ Mrp4 in mouse cells specifically enhanced nelfinavir and 9-(2-phosphonylmethoxyethyl) adenine cytotoxicity. These results suggest that nelfinavir is both an inhibitor and substrate of MRP4. Because nelfinavir is a new MRP4/ABCC4 substrate, we developed a MRP4/ABCC4 pharmacophore model, which showed that the nelfinavir binding site is shared with chemotherapeutic substrates such as adefovir and methotrexate. Our studies reveal, for the first time, that nelfinavir, a potent and cytotoxic PI, is both a substrate and inhibitor of MRP4. These findings suggest that HIV-infected cancer patients receiving nelfinavir might experience both enhanced antitumor efficacy and unexpected adverse toxicity given the role of MRP4/ABCC4 in exporting nucleoside-based antiretroviral medications and cancer chemotherapeutics.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Human Immunodeficiency Virus Protease Inhibitors Interact with ATP Binding Cassette Transporter 4/Multidrug Resistance Protein 4: A Basis for Unanticipated Enhanced Cytotoxicity

et al. 2013

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“…As HIV patients live longer, the occurrence of non-AIDSdefining malignancies has increased. In these patients antineoplastic therapy has to be used to effectively treat malignancy along with HAART therapy to maintain antiretroviral activity (Rudek et al, 2011;Malfitano et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Ritonavir and Efavirenz Significantly Alter the Metabolism of Erlotinib—an Observation in Primary Cultures of Human Hepatocytes That Is Relevant to HIV Patients with Cancer

et al. 2013

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Erlotinib is approved for the treatment of non-small cell lung and pancreatic cancers, and is metabolized by CYP3A4. Inducers and inhibitors of CYP3A enzymes such as ritonavir and efavirenz, respectively, may be used as part of the highly active antiretroviral therapy drugs to treat patients with human immunodeficiency virus (HIV). When HIV patients with a malignancy need treatment with erlotinib, there is a potential of as-yet-undefined drug-drug interaction. We evaluated these interactions using human hepatocytes benchmarked against the interaction of erlotinib with ketoconazole and rifampin, the archetype cytochrome P450 inhibitor and inducer, respectively. Hepatocytes were treated with vehicle [0.1% dimethylsulfoxide, ritonavir (10 mM)], ketoconazole (10 mM), efavirenz (10 mM), or rifampin (10 mM) for 4 days. On day 5, erlotinib (5 mM) was incubated with the above agents for another 24-48 hours. Concentrations of erlotinib and O-desmethyl erlotinib were quantitated in collected samples (combined lysate and medium) using liquid chromatography and tandem mass spectrometry. The half-life (t 1/2 ) of erlotinib increased from 10.6 6 2.6 to 153 6 80 and 23.9 6 4.8 hours, respectively, upon treatment with ritonavir and ketoconazole. The apparent intrinsic clearance (CL int, app ) of erlotinib was lowered 16-fold by ritonavir and 1.9-fold by ketoconazole. Efavirenz and rifampin decreased t 1/2 of erlotinib from 10.3 6 1.1 to 5.0 6 1.5 and 3.4 6 0.2 hours, respectively. Efavirenz and rifampin increased the CL int, app of erlotinib by 2.2-and 2-fold, respectively. Our results suggest that to achieve desired drug exposure, the clinically used dose (150 mg daily) of erlotinib may have to be significantly reduced (25 mg every other day) or increased (300 mg daily), respectively, when ritonavir or efavirenz is coadministered.

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“…The patient was treated with ART (lamivudine 300 mg/ day, abacavir sulfate 600 mg/day and raltegravir 800 mg/ day) for HIV because this regimen has the advantage of a relatively low frequency of adverse effects, such as unfavor- able interactions with antitumor drugs (11). Trimethoprim/ sulfamethoxazole and fluconazole were administered to prevent Pneumocystis jirovecii pneumonia and candidiasis.…”

Section: Introductionmentioning

confidence: 99%

Successful Treatment of Histiocytic Sarcoma and Concurrent HIV Infection Using a Combination of CHOP and Antiretroviral Therapy

et al. 2013

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Histiocytic sarcoma (HS) is a rare malignancy of soft tissues with an unknown etiology. The CHOP (cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride and prednisolone) regimen is often adopted as first-line chemotherapy; however, its therapeutic efficacy against HS is usually low. We herein first present the case of a patient with HS who was infected with human immunodeficiency virus-1 (HIV) in whom treatment with a combination of CHOP and antiretroviral therapy (ART) was successful. The patient has been in complete remission for 12 months following the discontinuation of chemotherapy under continuous ART. This case report may help to promote further investigation of both HS and HIV-related malignancy.

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Use of antineoplastic agents in patients with cancer who have HIV/AIDS

Cited by 124 publications

References 98 publications

Human Immunodeficiency Virus Protease Inhibitors Interact with ATP Binding Cassette Transporter 4/Multidrug Resistance Protein 4: A Basis for Unanticipated Enhanced Cytotoxicity

Human Immunodeficiency Virus Protease Inhibitors Interact with ATP Binding Cassette Transporter 4/Multidrug Resistance Protein 4: A Basis for Unanticipated Enhanced Cytotoxicity

Ritonavir and Efavirenz Significantly Alter the Metabolism of Erlotinib—an Observation in Primary Cultures of Human Hepatocytes That Is Relevant to HIV Patients with Cancer

Successful Treatment of Histiocytic Sarcoma and Concurrent HIV Infection Using a Combination of CHOP and Antiretroviral Therapy

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