AIDS-related Kaposi Research Articles

Current Status of Liposomal Anthracycline Therapy in Metastatic Breast Cancer

Doxorubicin is a mainstay for the treatment of metastatic breast cancer (MBC); however, its use is limited by toxicity, particularly cardiotoxicity. Novel drug delivery systems using liposomes have been developed to maintain the clinical utility of conventional doxorubicin while minimizing cardiotoxicity. Three liposomal anthracyclines have been developed: liposomal daunorubicin, nonpegylated liposomal doxorubicin, and pegylated liposomal doxorubicin. Liposomal daunorubicin, currently approved in the United States for the treatment of AIDS-related Kaposi sarcoma, has shown preliminary activity in MBC in a phase I trial; further investigation is ongoing. Nonpegylated liposomal doxorubicin, which is not available in the United States, has demonstrated activity similar to that of conventional doxorubicin (both as a single agent and in combinations). Pegylated liposomal doxorubicin has demonstrated activity in phase II and III trials when used alone or in combination with other chemotherapeutic agents in patients with MBC. It is currently approved in the United States and Europe for AIDS-related Kaposi sarcoma and platinum/paclitaxel-refractory ovarian carcinoma; in Europe and Canada, it is also approved as monotherapy for MBC. In addition, accumulating evidence suggests that the combination of liposomal anthracyclines (pegylated and nonpegylated) and trastuzumab is active, with acceptable toxicity. Based on these encouraging experiences, randomized clinical trials are ongoing or planned to further assess the therapeutic potential of pegylated liposomal doxorubicin as a single agent and in combination with other chemotherapeutic agents and targeted agents, such as trastuzumab, for MBC.

Paclitaxel for anthracycline-resistant AIDS-related Kaposi’s sarcoma: clinical and angiogenic correlations

BackgroundMurine data indicate that angiogenesis is central to the aetiopathogenesis of Kaposi’s sarcoma (KS). Therefore, we measured angiogenic cytokines and growth factors in patients with AIDS-related KS during treatment with both antiretrovirals and second-line paclitaxel chemotherapy. Cytokines measured included tumour necrosis factor-α (TNF-α), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and the interleukins IL-2, -6 and -12. Patients and methodsEnzyme-linked immunosorbent assays (ELISAs) were carried out to measure plasma cytokine levels in 17 patients with AIDS-related KS who had progressed within 6 months of receiving liposomal anthracyclines and were treated with paclitaxel 100 mg/m2 every 2 weeks. Measurements were carried out before progression, at commencement and at the completion of paclitaxel. ResultsThe objective response rate to paclitaxel was 71% (95% confidence interval 60% to 81%). In 17 patients with AIDS-related KS, we observed eight partial responses and four complete responses. Patients with AIDS Clinical Trial Group stage T1 disease had higher plasma VEGF (P = 0.05) and lower plasma TNF-α levels (P = 0.05) than patients with earlier stage T0 KS. There were no correlations between plasma cytokines (bFGF, VEGF, TNF-α, and IL-2,-6 and -12) and the CD4 and CD8 cell counts or HIV-1 RNA viral load. Response to paclitaxel was associated with a fall in plasma IL-6 levels (P = 0.04) but no change in other cytokines. There were no significant changes in CD4, CD8, CD16/56, CD19 cell counts and HIV-1 viral loads during chemotherapy. ConclusionsAngiogenic cytokines may correlate with KS disease extent but not with cellular immune function or HIV viraemia. Response to paclitaxel therapy correlates with a fall in plasma IL-6 levels and recent data indicate this may be a surrogate marker of KS-associated herpesvirus viral load. Overall, clinical response in KS correlates poorly with known angiogenic cytokines.

12E2: A Cloned Murine Dermal Cell with Features of Dermal Dendrocytes and Capacity to Produce Pathologic Changes Resembling Early Kaposi's Sarcoma

Factor XIIIa-positive dendrocytes are abundant within the dermis and have been implicated in the pathogenesis of various disorders, including AIDS-related Kaposi's sarcoma. Purified cultures of factor XIIIa-positive normal dermal dendrocytes have not as yet been achieved. 12E2 is a cloned cell line derived from superficial murine dermis where factor XIIIa-positive dendrocytes are abundant. Subconfluent cultures of 12E2 demonstrate polydendritic cell contours with thin, elongated membranous projections. These cells express Factor XIIIa and VCAM-1 by immunohistochemistry and by Western blot analysis of 12E2 cell lysates. 12E2 cells also constitutively express the Langerhans-cell-related epitope DEC-205, detected by NLDC-145 antibody and the CD80 co-stimulatory molecule, as well as Ia antigen on exposure to interferon-gamma. Cells so treated exhibit significant ability to present alloantigens in vitro. 12E2 cells are shown to express mRNA for numerous cytokines, including interleukin (IL)-1alpha, IL-1beta, IL-5, IL-6, IL-7, tumor necrosis factor-alpha and granulocyte macrophage-colony stimulating factor, by reverse-transcriptase polymerase chain reaction followed by Southern blot hybridization. Microinjection of 12E2 cells, but not 3T3control fibroblasts, into footpads of syngeneic and SCID mice results in lesions that mimic the histology and immunohistochemistry of human Kaposi's sarcoma. In aggregate, these data indicate that 12E2 cells 1) share lineage characteristics with factor XIIIa-positive dermal dendrocytes, 2) produce mRNA for numerous cytokines and are cytokine responsive to interferon-gamma, and 3) behave in vivo in a manner that resembles Kaposi's sarcoma, a condition known to involve proliferation of human dermal dendrocytes.

Nadir B cell counts are significantly correlated with the risk of Kaposi's sarcoma

Infection with HIV-1 is known to impair B cell function. To further elucidate the role of B cells during infection and tumorigenesis, we studied their numbers in cases of AIDS-related Kaposi's sarcoma (KS) during the HAART era. Patients with AIDS-related KS were identified from a database of 4,480 HIV-1 positive individuals and the incidence of KS and rate ratio was stratified according to nadir number of B cells, measured as the CD19 count. In an unadjusted model, we observed that lower B cell counts were associated with a statistically significant increased risk of KS development (p < 0.001). We also observed a trend toward increased counts during KS resolution. When adjusted for nadir CD4 count in a multi-variable model, higher B cell counts were protective against KS development (p = 0.015). These data highlight a potential role for B cells and therefore the humoral immune system in KS aetiopathogenesis.

Implications for oxidative and nitrative stress in the pathogenesis of AIDS-related Kaposi's sarcoma.

AIDS-related Kaposi's sarcoma (AIDS-KS), which is the most prevalent AIDS related cancer, arises in a unique environment characterized by profound immunosuppression in conjunction with sustained immunostimulation. Persistent inflammation and the accompanying increased production of reactive species can promote carcinogenesis by numerous routes including sustained cell proliferation, initiation of nuclear and mitochondrial DNA mutations and induction of a proangiogenic environment. Furthermore, during conditions of continuous inflammation, protein nitration can result in irreversible inactivation of enzymes including the cytoprotective and reactive species degrading enzyme, mitochondrial superoxide dismutase (MnSOD). Because MnSOD serves as a putative tumor suppressor gene in addition to its reactive species inactivating capacities, the loss of MnSOD's cytoprotective functions could markedly facilitate malignant transformation. The purpose of this study was to investigate biochemical and molecular pathways by which reactive species facilitate AIDS-KS pathogenesis. Immunohistochemical studies of AIDS-KS tumors showed intense AIDS-KS lesional cell staining for MnSOD, inducible nitric oxide synthase (NOS 2) and the presence of a cellular 'fingerprint' of nitrative stress, 3-nitrotyrosine. Collectively, these results that imply reactive species stress occurs in situ. Similarly, cultured AIDS-KS cells derived from the AIDS-KS tumors contained both MnSOD protein and the 'high output' isoform, NOS 2. Co-localization studies established that the mitochondria are a primary site for 3-nitrotyrosine localization and immunoprecipitation/immunoblotting experiments confirmed that MnSOD tyrosine nitration occurs in AIDS-KS cells. Functional SOD assays showed that AIDS-KS cells possess significantly lower MnSOD activity relative to matched control cells; findings which correspond with ongoing MnSOD tyrosine nitration and subsequent inactivation within AIDS-KS cells. These results, which show in situ evidence of reactive species stress within AIDS-KS tumors and functional deficits attributable to nitrative stress in tumor-derived AIDS-KS lesional cells, imply that reactive species are intimately associated with AIDS-KS pathogenesis and provide insights for development of novel strategies for AIDS-KS clinical treatments.

AIDS-related Kaposi's Sarcoma: evaluation of potential new prognostic factors and assessment of the AIDS Clinical Trial Group Staging System in the Haart Era--the Italian Cooperative Group on AIDS and Tumors and the Italian Cohort of Patients Naive From Antiretrovirals.

To assess potential new prognostic factors and to validate the AIDS Clinical Trials Group (ACTG) for AIDS-related Kaposi's sarcoma (AIDS-KS) staging system in the highly active antiretroviral therapy (HAART) era. We collected epidemiologic, clinical, staging, and survival data from 211 patients with AIDS-KS enrolled in two prospective Italian human immunodeficiency virus (HIV) cohort studies. We included in the analysis all patients with the diagnosis of KS made from January 1996, the time at which HAART became available in Italy. In the univariate analysis, survival was not influenced by sex, age, level of HIV viremia at KS diagnosis, HAART at KS diagnosis (HAART-naïve v HAART-experienced), or type of HAART combination. Regarding ACTG classification, the 3-year survival rate was 85% for T0 patients and 69% for T1 patients (P =.007), 83% for S0 patients and 63% for S1 patients (P =.003), and 83% for I0 patients and 71% for I1 patients (P =.06). In the multivariate analysis, only the combination of poor tumor stage (T1) and poor systemic disease (S1) risk identified patients with unfavorable prognosis. The 3-year survival rate of patients with T1S1 was 53%, which was significantly lower compared with the 3-year survival rates of patients with T0S0, T1S0, and T0S1, which were 88%, 80%, and 81%, respectively (P =.0001). In the era of HAART, a refinement of the original ACTG staging system is needed. CD4 level does not seem to provide prognostic information. Two different risk categories are identified: a good risk (T0S0, T1S0, T0S1) and a poor risk (T1S1).

From conventional to stealth liposomes: a new frontier in cancer chemotherapy.

Many attempts have been made to achieve good selectivity to targeted tumor cells by preparing specialized carrier agents that are therapeutically profitable for anticancer therapy. Among these, liposomes are the most studied colloidal particles thus far applied in medicine and in particular in antitumor therapy. Although they were first described in the 1960s, only at the beginning of 1990s did the first therapeutic liposomes appear on the market. The first-generation liposomes (conventional liposomes) comprised a liposome-containing amphotericin B, Ambisome (Nexstar, Boulder, CO, USA), used as an antifungal drug, and Myocet (Elan Pharma Int, Princeton, NJ, USA), a doxorubicin-containing liposome, used in clinical trials to treat metastatic breast cancer. The second-generation liposomes ("pure lipid approach") were long-circulating liposomes, such as Daunoxome, a daunorubicin-containing liposome approved in the US and Europe to treat AIDS-related Kaposi's sarcoma. The third-generation liposomes were surface-modified liposomes with gangliosides or sialic acid, which can evade the immune system responsible for removing liposomes from circulation. The fourth-generation liposomes, pegylated liposomal doxorubicin, were called "stealth liposomes" because of their ability to evade interception by the immune system, in the same way as the stealth bomber was able to evade radar. Actually, the only stealth liposome on the market is Caelyx/Doxil (Schering-Plough, Madison NJ, USA), used to cure AIDS-related Kaposi's sarcoma, resistant ovarian cancer and metastatic breast cancer. Pegylated liposomal doxorubicin is characterized by a very long-circulation half-life, favorable pharmacokinetic behavior and specific accumulation in tumor tissues. These features account for the much lower toxicity shown by Caelyx in comparison to free doxorubicin, in terms of cardiotoxicity, vesicant effects, nausea, vomiting and alopecia. Pegylated liposomal doxorubicin also appeared to be less myelotoxic than doxorubicin. Typical forms of toxicity associated to it are acute infusion reaction, mucositis and palmar plantar erythrodysesthesia, which occur especially at high doses or short dosing intervals. Active and cell targeted liposomes can be obtained by attaching some antigen-directed monoclonal antibodies (Moab or Moab fragments) or small proteins and molecules (folate, epidermal growth factor, transferrin) to the distal end of polyethylene glycol in pegylated liposomal doxorubicin. The most promising therapeutic application of liposomes is as non-viral vector agents in gene therapy, characterized by the use of cationic phospholipids complexed with the negatively charged DNA plasmid. The use of liposome formulations in local-regional anticancer therapy is also discussed. Finally, pegylated liposomal doxorubicin containing radionuclides are used in clinical trials as tumor-imaging agents or in positron emission tomography.

AIDS‐related Kaposi's sarcoma cells rapidly internalize endostatin, which co‐localizes to tropomysin microfilaments and inhibits cytokine‐mediated migration and invasion

AIDS-related Kaposi's sarcoma (KS) is the most common HIV-related malignancy. In some respects, KS is analogous to other angioproliferative diseases, in that KS lesions are highly vascularized and promoted by inflammatory cytokines. However, unlike other cancers or inflammatory mediated vascular diseases, KS is unique in that the KS lesional cells both express and respond to the complete angiogenic cytokines vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). Therefore, the angiogenic phenotype, which is crucial for cancer progression, is inherent to KS tumor cells. Due to the recognized importance of angiogenesis in cancer progression, numerous angiostatic agents are being investigated as potential therapeutic agents. One such agent is endostatin, which is a 20-kDa carboxyl-terminal fragment of collagen XVIII that has demonstrated potent angiostatic activities at both the in vivo and in vitro levels. Since endostatin is recognized as a potent angiostatic agent, the majority of in vitro endostatin studies have evaluated its effects on endothelial cells. Although KS cells are speculated to arise from endothelial cell precursors and KS lesions are highly vascularized, no previous studies have investigated endostatin-KS cell interactions. This present study evaluated endostatin's effects on KS tumor cell: (i) signal transduction (endostatin internalization and transcription factor activation), and (ii) migration and invasion (functional activity assays and tropomysin co-localization). Our results show that KS cells rapidly internalize endostatin and that endostatin initiates activation of the transcription activating factors nuclear factor-kappaB (NF-kappaB) and activating protein 1 (AP-1). Our data also show that internalized endostatin co-localizes to tropomysin microfilaments and acts to inhibit KS cell migration and invasion in response to the clinically relevant angiogenic cytokines VEGF and bFGF. As a consequence of its combined angiostatic and antitumorigenic activities, endostatin could provide dual therapeutic benefits for patients with mucocutaneous KS.

Immune activation in AIDS related Kaposi's sarcoma

To study the pathogenesis role of immune system activation in AIDS related Kaposi's sarcoma(AIDS-KS). The serum levels of sFas, beta 2-microglobin, IL-10, IL-16, IL-18, IL-6 and sIL-4R were detected by ELISA in 8 AIDS-KS patients, 28 patients with HIV infection but without Kaposi's sarcoma(HIV-NKS) and 16 normal controls. The lymphocyte and their subsets, CD38(+) CD8, HLA-DR(+)CD8 in the peripheral blood mononuclear cell (PBMCs) in 12 AIDS-KS and 32 HIV-NKS were detected by flow cytometer. Beta 2-MG and sIL-4R in HIV-NKS were significantly higher than those in normal controls(P<0.05), IL-16 in HIV-NKS was significantly lower than that in controls(P<0.05). IL-18 was higher in both AIDS-KS and HIV-NKS compared with normal controls. In AIDS-KS, CD3, CD4, CD8, NK and HLA-DR(+)CD8 were lower than those in HIV-NKS whereas CD19 and CD38(+)CD8 were higher than those in HIV-NKS. But the difference was not statistically(P<0.05). Although both AIDS-KS and HIV-NKS demonstrate some activation of immune system, there appears to be no significant difference between immune responses in KS and NKS patients. These data suggest that the activation of the immune system is unlikely to contribute significantly to the pathogenesis of AIDS-KS.

Gene expression profile of AIDS-related Kaposi's sarcoma.

BackgroundKaposi's Sarcoma (KS) is a proliferation of aberrant vascular structures lined by spindle cells, and is caused by a gammaherpes virus (HHV8/KSHV). Its course is aggravated by co-infection with HIV-1, where the timing of infection with HIV-1 and HHV8 is important for the clinical outcome.MethodsIn order to better understand the pathogenesis of KS, we have analysed tissue from two AIDS-KS lesions, and from normal skin by serial analysis of gene expression (SAGE). Semi-quantitative RT-PCR was then used to validate the results.ResultsThe expression profile of AIDS-related KS (AIDS-KS) reflects an active process in the skin. Transcripts of HHV8 were found to be very low, and HIV-1 mRNA was not detected by SAGE, although it could be found using RT-PCR. Comparing the expression profile of AIDS-KS tissue with publicly available SAGE libraries suggested that AIDS-KS mRNA levels are most similar to those in an artificially mixed library of endothelial cells and leukocytes, in line with the description of KS lesions as containing spindle cells with endothelial characteristics, and an inflammatory infiltrate. At least 64 transcripts were found to be significantly elevated, and 28 were statistically downregulated in AIDS-KS compared to normal skin. Five of the upregulated mRNAs, including Tie 1 and sialoadhesin/CD169, were confirmed by semi-quantitative PCR to be elevated in additional AIDS-KS biopsies. Antibodies to sialoadhesin/CD169, a known marker of activated macrophages, were shown to specifically label tumour macrophages.ConclusionThe expression profile of AIDS-KS showed 64 genes to be significantly upregulated, and 28 genes downregulated, compared with normal skin. One of the genes with increased expression was sialoadhesin (CD169). Antibodies to sialoadhesin/CD169 specifically labelled tumour-associated macrophages, suggesting that macrophages present in AIDS-KS lesions belong to a subset of human CD169+ macrophages.

Pharmacokinetics of pegylated liposomal Doxorubicin: review of animal and human studies.

Pegylated liposomal doxorubicin (doxorubicin HCl liposome injection; Doxil or Caelyx) is a liposomal formulation of doxorubicin, reducing uptake by the reticulo-endothelial system due to the attachment of polyethylene glycol polymers to a lipid anchor and stably retaining drug as a result of liposomal entrapment via an ammonium sulfate chemical gradient. These features result in a pharmacokinetic profile characterised by an extended circulation time and a reduced volume of distribution, thereby promoting tumour uptake. Preclinical studies demonstrated one- or two-phase plasma concentration-time profiles. Most of the drug is cleared with an elimination half-life of 20-30 hours. The volume of distribution is close to the blood volume, and the area under the concentration-time curve (AUC) is increased at least 60-fold compared with free doxorubicin. Studies of tissue distribution indicated preferential accumulation into various implanted tumours and human tumour xenografts, with an enhancement of drug concentrations in the tumour when compared with free drug. Clinical studies of pegylated liposomal doxorubicin in humans have included patients with AIDS-related Kaposi's sarcoma (ARKS) and with a variety of solid tumours, including ovarian, breast and prostate carcinomas. The pharmacokinetic profile in humans at doses between 10 and 80 mg/m(2) is similar to that in animals, with one or two distribution phases: an initial phase with a half-life of 1-3 hours and a second phase with a half-life of 30-90 hours. The AUC after a dose of 50 mg/m(2) is approximately 300-fold greater than that with free drug. Clearance and volume of distribution are drastically reduced (at least 250-fold and 60-fold, respectively). Preliminary observations indicate that utilising the distinct pharmacokinetic parameters of pegylated liposomal doxorubicin in dose scheduling is an attractive possibility. In agreement with the preclinical findings, the ability of pegylated liposomes to extravasate through the leaky vasculature of tumours, as well as their extended circulation time, results in enhanced delivery of liposomal drug and/or radiotracers to the tumour site in cancer patients. There is evidence of selective tumour uptake in malignant effusions, ARKS skin lesions and a variety of solid tumours. The toxicity profile of pegylated liposomal doxorubicin is characterised by dose-limiting mucosal and cutaneous toxicities, mild myelosuppression, decreased cardiotoxicity compared with free doxorubicin and minimal alopecia. The mucocutaneous toxicities are dose-limiting per injection; however, the reduced cardiotoxicity allows a larger cumulative dose than that acceptable for free doxorubicin. Thus, pegylated liposomal doxorubicin represents a new class of chemotherapy delivery system that may significantly improve the therapeutic index of doxorubicin.

Cardiovascular manifestations of HIV infection.

Studies published over the past 3 years have tracked the incidence and course of human immunodeficiency virus (HIV) infection in relation to cardiac illness in both children and adults.1 These studies show that subclinical echocardiographic abnormalities independently predict adverse outcomes and identify high-risk groups to target for early intervention and therapy. The Joint United Nations Program on HIV/AIDS estimates that 36.1 million people were living with HIV infection at the end of the year 2000.2 If 8% to 10% of patients develop symptomatic heart failure over a 2- to 5-year period,3 then 3 million cases of HIV-related heart failure will present during that period.1 Cardiovascular manifestations of HIV have been altered by the introduction of highly active antiretroviral therapy (HAART) regimens. On one hand, HAART has significantly modified the course of HIV disease, lengthened survival, and improved the quality of life of HIV-infected patients. On the other hand, the early data have raised concerns that HAART is associated with an increase in both peripheral and coronary arterial diseases.1 The HAART-associated changes are relevant only to the minority of HIV-infected individuals worldwide who have access to HAART. Thus, studies conducted before HAART became available remain globally applicable. In this review article, the principal HIV-associated cardiovascular manifestations will be discussed, with an emphasis on new knowledge about prevalence, pathogenesis, and treatment. HIV disease is recognized as an important cause of dilated cardiomyopathy, with an estimated annual incidence of 15.9 in 1000 before the introduction of HAART3 (Table 1). The importance of cardiac dysfunction is demonstrated by its effect on survival in acquired immunodeficiency syndrome (AIDS). Median survival to AIDS-related death is 101 days in patients with left ventricular dysfunction and 472 days in patients with a normal heart as shown by echocardiography at a similar infection …

Acquired elastotic hemangioma: A clinicopathologic variant of hemangioma

Background: In recent years, many new cutaneous vascular proliferations have been described. This is partly due to the current epidemic of AIDS, which has forced dermatopathologists to establish the diagnosis of the earliest patch-stage lesions of AIDS-related Kaposi's sarcoma and some of the recently described cutaneous vascular proliferations that may histopathologically mimic lesions of early Kaposi's sarcoma. Objective: This article reports the clinical, histopathologic, and immunohistochemical findings in 6 cases of a clinicopathologic variant of cutaneous hemangioma, which we have named acquired elastotic hemangioma. Methods: Six cases of acquired elastotic hemangioma were studied from clinical, histopathologic, and immunohistochemical standpoints. The histopathologic differential diagnosis with other similar cutaneous vascular proliferations is discussed. Results: Acquired elastotic hemangioma appears on the sun-damaged skin of the dorsal aspect of the forearms or on the lateral aspects of the neck of middle-aged or elderly women. Clinically, lesions present as solitary erythematous plaques with variable morphology and in only some cases have a clearly angiomatous appearance. On histopathologic examination, acquired elastotic hemangioma is characterized by a band-like proliferation of capillary blood vessels involving the superficial dermis and arranged horizontally parallel to the epidermis. Conclusion: Acquired elastotic hemangioma is a distinctive clinicopathologic variant of hemangioma that should be differentiated from other cutaneous vascular proliferations. On histopathologic examination, it is characterized by capillary proliferation involving the dermis. (J Am Acad Dermatol 2002;47:371-6.)

Vascular endothelial growth factor levels in serum do not increase following HIV type 1 and HHV8 seroconversion and lack correlation with AIDS-related Kaposi's sarcoma.

The utility of vascular endothelial growth factor (VEGF) concentrations in serum as a predictive marker for AIDS-KS was studied. Sera were obtained from 40 homosexual men who seroconverted for HIV-1 and HHV8 prior to or during their participation in the Amsterdam Cohort Studies (1984-2000). We designed an ELISA to detect VEGF and measured VEGF prior to either infection, at HIV-1 and HHV8 seroconversion, after both infections, at AIDS-KS diagnosis (n = 11), and in the most recently available serum sample. The geometric mean serum VEGF concentration was 81.5 pg/ml in those with AIDS-KS and 80.4 pg/ml in those with AIDS but without KS. Median serum VEGF concentrations did not differ between the time points described above. Higher VEGF concentrations in serum were observed at higher CD4(+) cell counts. Serum concentrations of VEGF were not influenced by HIV-1 or HHV8 infection or by the conditions leading to AIDS-KS. Sequential measurement of VEGF in serum is not expected to contribute to the prediction or therapeutic monitoring of AIDS-KS.

Human–bacteria nitric oxide cycles in HIV-1 infection

The human intestinal tract harbors a complex microbiotic environment containing commensal bacteria and immunocompetent mucosal cells. There is considerable communication between the bacteria and host cells through dietary constituents and metabolic cycles. We propose that in the pathogenesis of acquired immunodeficiency syndrome (AIDS), the human immunodeficiency virus-1 (HIV-1) triggers a change in a coupled transorganism (human–bacteria) nitric oxide interchange cycle, that may influence the biosynthesis and recycling of nitric oxide (NO) in AIDS patients. Normally, nitric oxide (NO) is produced from arginine through nitrate NO3−, which is ultimately eliminated in the urine and feces. In HIV infection, however, the NO3− is converted into NO and nitrite NO2− and recirculated in the body, perhaps as a result of concomitant opportunistic bacterial infections and cellular hypoxia. Due to the efficient coupling of the human–bacteria nitric oxide cycles, persistently high levels of nitrite and the free radicals peroxynitrite (ONOO−) may occur in AIDS patients, contributing to the etiology of AIDS-related dementia, persistent immunosuppression and Kaposi's sarcoma

Caelyx/Doxil for the treatment of metastatic ovarian and breast cancer

Caelyx/Doxil is a novel pegylated liposomal formulation of the first-generation anthracycline, doxorubicin. The pharmacokinetics of this polyethylene-glycol-coated liposome are characterized by a reduced volume of distribution, a long intravascular circulating half-life and slow plasma clearance compared with free doxorubicin. This, coupled with a small vesicular size, uniquely promotes the localization of Caelyx/Doxil at tumor sites and explains its altered toxicity profile. The FDA and EMEA have approved its use for the treatment of AIDS-related Kaposi’s sarcoma and, more recently, for recurrent epithelial ovarian cancer. Numerous investigations have focused on its use in the treatment of metastatic breast cancer, as well as recurrent squamous cell cervical carcinoma, soft tissue sarcoma, squamous head and neck cancers, prostate cancers and malignant gliomas. Ongoing clinical studies of combination regimens incorporating Caelyx/Doxil will further clarify its role in the treatment of advanced solid tumours.

Polyethylene Glycol-Liposomal Doxorubicin

Polyethylene glycol (PEG)-liposomal doxorubicin is a formulation of the anthracycline doxorubicin in which the drug is encapsulated in PEG-coated liposomes. This alters the pharmacokinetic properties of doxorubicin, prolonging circulation time and enhancing localisation to tumours. In a large randomised trial, intravenous PEG-liposomal doxorubicin was at least as effective as topotecan in patients with ovarian cancer refractory or sensitive to first-line platinum-based chemotherapy. Overall response rates of patients with ovarian cancer refractory to platinum- and paclitaxel-based chemotherapy who received the drug ranged from 18.3 to 27.6% in noncomparative clinical trials. PEG-liposomal doxorubicin also has antitumour activity in patients with metastatic breast cancer pretreated with other chemotherapeutic agents. Overall response rates were similar in patients with pretreated metastatic breast cancer who had received PEG-liposomal doxorubicin or two comparator salvage chemotherapy regimens (vinorelbine or mitomycin C plus vinblastine) in an interim analysis of a large randomised study. In patients with advanced AIDS-related Kaposi's sarcoma, PEG-liposomal doxorubicin monotherapy produced overall response rates ranging from 46 to 77% in randomised trials. The drug was significantly more effective than bleomycin plus vincristine alone or in combination with standard doxorubicin, as measured by tumour response. As a replacement for standard doxorubicin in commonly used combination therapies, PEG-liposomal doxorubicin has shown activity in multiple myeloma and aggressive non-Hodgkin's lymphoma in small, preliminary trials. The most common adverse events associated with PEG-liposomal doxorubicin are myelosuppression, palmar-plantar erythrodysaesthesia, stomatitis and nausea. These can be managed by delaying or reducing dosages. Although preliminary trials are promising, the relative cardiotoxicity of PEG-liposomal doxorubicin compared with the standard formulation has not been clearly established. Monotherapy with PEG-liposomal doxorubicin is effective as a second-line chemotherapy in patients with platinum-refractory ovarian cancer and in patients with metastatic breast cancer. However, as with all chemotherapeutic agents, the benefits of treatment need to be weighed against the agent's tolerability profile. Strong comparative data have helped to establish PEG-liposomal doxorubicin as the first-line treatment option in patients with advanced Kaposi's sarcoma. Anticancer activity has also been observed in studies conducted in small numbers of patients with multiple myeloma or non-Hodgkin's lymphoma receiving PEG-liposomal doxorubicin instead of standard doxorubicin in combination regimens, although further data are needed to confirm the clinical relevance of these findings.

Matrix Metalloproteinase Inhibitor COL-3 in the Treatment of AIDS-Related Kaposi's Sarcoma: A Phase I AIDS Malignancy Consortium Study

PURPOSE: Matrix metalloproteinases (MMPs) are involved in tumor invasion and metastasis and are overexpressed in Kaposi’s sarcoma (KS) cells. The primary aim was to define the safety and toxicity of the MMP inhibitor COL-3 in patients with AIDS-related KS. Secondary aims were to evaluate tumor response, pharmacokinetics, and changes in blood levels of MMP-2, MMP-9, vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF). PATIENTS AND METHODS: COL-3 was administered orally once daily, and doses were escalated in cohorts of three to six subjects. Patients with symptomatic visceral KS or severe tumor-associated edema were excluded. Antiretroviral therapy was permitted but not required. Study end points were grade 3 or 4 toxicity or progressive KS. Serial blood specimens were obtained for pharmacokinetics and levels of MMP-2, MMP-9, VEGF, and bFGF. RESULTS: Eighteen patients received COL-3 in dosing cohorts of 25, 50, and 70 mg/m2/d. Prior KS therapy was reported by 17 patients (9...

Recent advances in the treatment of AIDS-related Kaposi's sarcoma.

Kaposi's sarcoma (KS) is the most common malignancy associated with HIV infection and is considered an AIDS defining condition by the US Centers of Disease Control Guidelines. Several advances in the treatment of AIDS-related KS have been achieved over the past few years, even though a gold standard therapy for KS has not yet been defined and treatment must be tailored to individual needs. Since the availability of highly active antiretroviral therapy (HAART), a dramatic clinical response has been documented in patients with KS, making HAART an essential approach in the management of KS in most, if not all, patients with AIDS-related KS. However, in case of aggressive, visceral, and/or life-threatening KS, more complex therapeutic schedules have to be taken into account, including chemotherapy, radiotherapy, and/or immunotherapy. In general, systemic treatment for KS is limited to widespread, symptomatic disease, whereas local interventions are indicated for minimal, cosmetically troublesome lesions. Among new cytotoxic agents, liposomal anthracyclines and paclitaxel are highly effective molecules for KS and have been approved by the US Food and Drug Administration (FDA) as first-line and second-line monotherapy, respectively, for advanced KS. Furthermore, a greater understanding of the pathogenesis of KS has lead to the development of an array of new experimental agents. Many antiangiogenic agents such as AGM 1470 (TNP 470), thalidomide, and glufanide disodium (IM 862) have produced encouraging responses in patients with KS and large clinical trials are in progress. Retinoic acids may also block neoangiogenesis as well as proliferation of KS cells in vitro, and they have been used either systemically or topically with a high response rate. Thus, a topical compound 0.1% alitretinoin gel was approved in 1999 by the FDA for the treatment of skin lesions associated with KS. Human chorionic gonadotropin, a hormonal agent, has shown a strong inhibitory activity in KS cells, but its role in the regression of KS lesions is not clear. Finally, the identification of a novel gamma-herpesvirus, human herpesvirus-8, as a causative agent for KS, together with novel antiangiogenic compounds, such as metalloproteinase inhibitors, may offer promising targets for the therapy of KS.

BILATERAL ADRENAL KAPOSI’S SARCOMA IN AN HIV SERONEGATIVE PATIENT

Visceral Kaposi’s sarcoma in the absence of mucocutaneous lesions is uncommon. Asymptomatic adrenal gland involvement associated with many other localizations has been reported occasionally in AIDS related Kaposi’s sarcoma.1 We report a case of apparently exclusive bilateral adrenal Kaposi’s sarcoma in an HIV seronegative black patient.