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HIV protease inhibitors have specific anti-cancer effects
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Notes / Biomed Pharmacother 56 (2002) 423–425
HIV protease inhibitors have specific anti-cancer effects The HIV protease inhibitors (PI) are new potent antiretroviral drugs, which inhibit HIV replication by blocking in a very specific way a ‘key’ viral protein, the HIV protease. Since the introduction of PI in highly active anti-retroviral combination therapies (HAART), a significant reduction of Kaposi’s sarcoma (KS) incidence has been noted and even lesion regression in PI-treated patients. KS is an angioproliferative cancer that is particularly frequent and aggressive in HIV-infected individuals, but also present in HIVnegative persons [Ensoli et al., Adv. Cancer Res. (2001)]. Although the effects of PI on KS were originally attributed to their antiviral activities, epidemiologists could not draw a clear correlation between HIV suppression by PI, recovery of the immune system, and KS regression. Moreover, it was soon evident that PI were endowed with unpredicted effects on cell and lipid metabolism. This and the fact that KS is an angio-proliferative disease (composed by blood vessels and proliferating cells of endothelial origin) suggested to us that PI blocked specific mechanisms related to cancer and angiogenesis, which involve a variety of proteases. Therefore, we investigated the possible effects of PI on angiogenesis and KS. The results of these studies [Sgadari et al., Nature Med 8 (2002) 225–32] indicated that PI are potent antiangiogenic and antitumor molecules and that they block cell proteases that are required for angiogenesis and invasion of tumor cells, which are called matrix metalloproteases. Since tumor growth requires blood supply through newly formed vessels, the dual block of angiogenesis and tumor cell invasion by PI results in a potent inhibition of tumor development or in tumor regression. This indicates that PI should be exploited in the therapy of cancers in general, and that should always be included in the therapy of HIV-infected patients at risk for tumor development. In particular, these drugs have already been shown to be safe and effective for human use; therefore, they can be quickly developed also for treatment of different tumors or angiogenic diseases in both HIVseronegative and -seropositive individuals. This is supported by the results of recent studies on the efficacy of established broad-spectrum MMP inhibitors in human diseases. Based on these results, we are organizing an Italian multi-centric clinical trial with PI for the treatment of KS developing in HIV-negative patients. This will open the use of PI in the therapy of cancers and diseases associated with angiogenesis independently of the HIV status. B. Ensoli Istitute Superiore di Sanita, Rome, Italy
> Nature Medicine 2002;8:225–8.
PII: S 0 7 5 3 - 3 3 2 2 ( 0 2 ) 0 0 2 6 9 - X
Adult stem cells in retinopathy Grant et al. report on the confirmation that adult bone marrow-derived hematopoietic stem cells (HSC) may form not only blood cells, but also vascular tissue, thus qualifying them as adult hemangioblasts. Using purified HSC expressing green fluorescent protein (gfp) from transgenic animals as donor tissue for bone marrow reconstitution, they showed that gfp-expressing cells home to sites of ischemic injury in the retinal vasculature where they transdifferentiate into functional endothelium and help form functional blood vessels. Long-term, durable reconstitution, serial transplantation, and single-cell reconstitution established that HSCs function as hemangioblasts. The model system was developed to examine new vessel growth in the adult retina resulting from ischemia as may be found in diabetic retinopathy. The results confirm that circulating precursor cells, in addition to resident cells, are an important component of neovascular growth in response to ischemic injury. These findings highlight a previously unappreciated component of postnatal vascular development and could lead to new avenues for developing therapies to combat proliferative vasculopathies. M.B. Grant Shands Cancer Center, University of Florida, Gainesville, FL, USA
> Nature Medicine 2002;8:607–12.
PII: S 0 7 5 3 - 3 3 2 2 ( 0 2 ) 0 0 2 7 0 - 6
Lopinavir/ritonavir versus nelfinavir therapy for HIV In a head-to-head randomized trial between two antiretroviral drugs combinations, Walmsley and her coresearchers found that a combination containing the protease inhibitor lopinavir and ritonavir proved more effective than a similar antiretroviral combination containing nelfinavir, the most commonly used protease inhibitor. The protease inhibitors are a class of antiretroviral (antiHIV) agents, which help prevent the HIV virus from maturing and replicating. In the new drug, a small dose of ritonavir slows the metabolism of lopinavir in the body, thereby ‘boosting’ the levels of lopinavir in the bloodstream increasing its potency and prolonging its effectiveness.
Notes / Biomed Pharmacother 56 (2002) 423–425
HIV protease inhibitors have specific anti-cancer effects The HIV protease inhibitors (PI) are new potent antiretroviral drugs, which inhibit HIV replication by blocking in a very specific way a ‘key’ viral protein, the HIV protease. Since the introduction of PI in highly active anti-retroviral combination therapies (HAART), a significant reduction of Kaposi’s sarcoma (KS) incidence has been noted and even lesion regression in PI-treated patients. KS is an angioproliferative cancer that is particularly frequent and aggressive in HIV-infected individuals, but also present in HIVnegative persons [Ensoli et al., Adv. Cancer Res. (2001)]. Although the effects of PI on KS were originally attributed to their antiviral activities, epidemiologists could not draw a clear correlation between HIV suppression by PI, recovery of the immune system, and KS regression. Moreover, it was soon evident that PI were endowed with unpredicted effects on cell and lipid metabolism. This and the fact that KS is an angio-proliferative disease (composed by blood vessels and proliferating cells of endothelial origin) suggested to us that PI blocked specific mechanisms related to cancer and angiogenesis, which involve a variety of proteases. Therefore, we investigated the possible effects of PI on angiogenesis and KS. The results of these studies [Sgadari et al., Nature Med 8 (2002) 225–32] indicated that PI are potent antiangiogenic and antitumor molecules and that they block cell proteases that are required for angiogenesis and invasion of tumor cells, which are called matrix metalloproteases. Since tumor growth requires blood supply through newly formed vessels, the dual block of angiogenesis and tumor cell invasion by PI results in a potent inhibition of tumor development or in tumor regression. This indicates that PI should be exploited in the therapy of cancers in general, and that should always be included in the therapy of HIV-infected patients at risk for tumor development. In particular, these drugs have already been shown to be safe and effective for human use; therefore, they can be quickly developed also for treatment of different tumors or angiogenic diseases in both HIVseronegative and -seropositive individuals. This is supported by the results of recent studies on the efficacy of established broad-spectrum MMP inhibitors in human diseases. Based on these results, we are organizing an Italian multi-centric clinical trial with PI for the treatment of KS developing in HIV-negative patients. This will open the use of PI in the therapy of cancers and diseases associated with angiogenesis independently of the HIV status. B. Ensoli Istitute Superiore di Sanita, Rome, Italy
> Nature Medicine 2002;8:225–8.
PII: S 0 7 5 3 - 3 3 2 2 ( 0 2 ) 0 0 2 6 9 - X
Adult stem cells in retinopathy Grant et al. report on the confirmation that adult bone marrow-derived hematopoietic stem cells (HSC) may form not only blood cells, but also vascular tissue, thus qualifying them as adult hemangioblasts. Using purified HSC expressing green fluorescent protein (gfp) from transgenic animals as donor tissue for bone marrow reconstitution, they showed that gfp-expressing cells home to sites of ischemic injury in the retinal vasculature where they transdifferentiate into functional endothelium and help form functional blood vessels. Long-term, durable reconstitution, serial transplantation, and single-cell reconstitution established that HSCs function as hemangioblasts. The model system was developed to examine new vessel growth in the adult retina resulting from ischemia as may be found in diabetic retinopathy. The results confirm that circulating precursor cells, in addition to resident cells, are an important component of neovascular growth in response to ischemic injury. These findings highlight a previously unappreciated component of postnatal vascular development and could lead to new avenues for developing therapies to combat proliferative vasculopathies. M.B. Grant Shands Cancer Center, University of Florida, Gainesville, FL, USA
> Nature Medicine 2002;8:607–12.
PII: S 0 7 5 3 - 3 3 2 2 ( 0 2 ) 0 0 2 7 0 - 6
Lopinavir/ritonavir versus nelfinavir therapy for HIV In a head-to-head randomized trial between two antiretroviral drugs combinations, Walmsley and her coresearchers found that a combination containing the protease inhibitor lopinavir and ritonavir proved more effective than a similar antiretroviral combination containing nelfinavir, the most commonly used protease inhibitor. The protease inhibitors are a class of antiretroviral (antiHIV) agents, which help prevent the HIV virus from maturing and replicating. In the new drug, a small dose of ritonavir slows the metabolism of lopinavir in the body, thereby ‘boosting’ the levels of lopinavir in the bloodstream increasing its potency and prolonging its effectiveness.