Multicenter phase 1/2 study of forodesine in patients with relapsed peripheral T cell lymphoma.

Peripheral T cell lymphomas are an aggressive group of non-Hodgkin lymphomas with poor outcomes for most subtypes and no accepted standard of care for relapsed patients. This study evaluated the efficacy and safety of forodesine, a novel purine nucleoside phosphorylase inhibitor, in patients with relapsed peripheral T cell lymphomas. Patients with histologically confirmed disease, progression after ≥ 1 prior treatment, and an objective response to last treatment received oral forodesine 300 mg twice-daily. The primary endpoint was objective response rate (ORR). Secondary endpoints included duration of response, progression-free survival (PFS), overall survival (OS), and safety. Forty-eight patients (median age, 69.5 years; median of 2 prior treatments) received forodesine. In phase 1 (n = 3 evaluable), no dose-limiting toxicity was observed during the first 28 days of forodesine treatment. In phase 2 (n = 41 evaluable), the ORR for the primary and final analyses was 22% (90% CI 12-35%) and 25% (90% CI 14-38%), respectively, including four complete responses (10%). Median PFS and OS were 1.9 and 15.6 months, respectively. The most common grade 3/4 adverse events were lymphopenia (96%), leukopenia (42%), and neutropenia (35%). Dose reduction and discontinuation due to adverse events were uncommon. Secondary B cell lymphoma developed in five patients, of whom four were positive for Epstein-Barr virus. In conclusion, forodesine has single-agent activity within the range of approved therapies in relapsed peripheral T cell lymphomas, with a manageable safety profile, and may represent a viable treatment option for this difficult-to-treat population.

Forodesine in the treatment of cutaneous T-cell lymphoma.

INTRODUCTION: Cutaneous T-cell lymphoma (CTCL) is characterized by the accumulation of neoplastic CD4+ T lymphocytes in the skin. Given the lack of curative treatments for CTCL, there is a significant need for new, superior therapies. Forodesine is a transition-state analogue that inhibits purine nucleoside phosphorylase. Because it selectively targets T lymphocytes, it represents a drug of interest for the treatment of CTCL. Areas covered: Phase I/II dose-ranging studies of intravenous (IV) and oral forodesine demonstrated its activity, safety, and tolerability for refractory CTCL. Response rates were 31% and 27%, respectively. No dose-limiting toxicities were observed. These studies were followed by a phase II trial of oral forodesine 200 mg daily. This oral formulation showed only partial activity, with a response rate of 11%, likely attributable to underdosing. Common adverse events in these trials included infection, fatigue, peripheral edema, nausea, pruritus, headache, and insomnia. Expert opinion: IV and oral formulations of forodesine have demonstrated partial activity and an acceptable safety profile in patients with refractory CTCL. A higher oral dose, or sequential therapy consisting of IV forodesine followed by maintenance oral forodesine, may be more effective. With proper dosing, forodesine may emerge as a safe and effective treatment for refractory CTCL.

Immucillins ImmA and ImmH Are Effective and Non-toxic in the Treatment of Experimental Visceral Leishmaniasis.

BACKGROUND: Immucillins ImmA (IA), ImmH (IH) and SerMe-ImmH (SMIH) are synthetic deazapurine nucleoside analogues that inhibit Leishmania (L.) infantum chagasi and Leishmania (L.) amazonensis multiplication in vitro without macrophage toxicity. Immucillins are compared to the Glucantime standard drug in the chemotherapy of Leishmania (L.) infantum chagasi infection in mice and hamsters. These agents are tested for toxicity and immune system response. METHODOLOGY/PRINCIPAL FINDINGS: BALB/c mice were infected with 107 amastigotes, treated with IA, IH, SMIH or Glucantime (2.5mg/kg/day) and monitored for clinical variables, parasite load, antibody levels and splenocyte IFN-γ, TNF-α, and IL-10 expression. Cytokines and CD4+, CD8+ and CD19+ lymphocyte frequencies were assessed in uninfected controls and in response to immucillins. Urea, creatinine, GOT and GPT levels were monitored in sera. Anti-Leishmania-specific IgG1 antibodies (anti-NH36) increased in untreated animals. IgG2a response, high levels of IFN-γ, TNF-α and lower levels of IL-10 were detected in mice treated with the immucillins and Glucantime. Immucillins permitted normal weight gain, prevented hepato-splenomegaly and cleared the parasite infection (85-89%) without renal and hepatic toxicity. Immucillins promoted 35% lower secretion of IFN-γ in uninfected controls than in infected mice. IA and IH increased the CD4+ T and CD19+ B cell frequencies. SMIH increased only the proportion of CD-19 B cells. IA and IH also cured infected hamsters with lower toxicity than Glucantime. CONCLUSIONS/SIGNIFICANCE: Immucillins IA, IH and SMIH were effective in treating leishmaniasis in mice. In hamsters, IA and IH were also effective. The highest therapeutic efficacy was obtained with IA, possibly due to its induction of a TH1 immune response. Low immucillin doses were required and showed no toxicity. Our results disclose the potential use of IA and IH in the therapy of visceral leishmaniasis.

Final results of a multicenter phase II study of the purine nucleoside phosphorylase (PNP) inhibitor forodesine in patients with advanced cutaneous T-cell lymphomas (CTCL) (Mycosis fungoides and Sézary syndrome).

BACKGROUND: Forodesine is a potent inhibitor of purine nucleoside phosphorylase (PNP) that leads to intracellular accumulation of deoxyguanosine triphosphate (dGTP) in T and B cells, resulting in apoptosis. Forodesine has demonstrated impressive antitumor activity in early phase clinical trials in cutaneous T-cell lymphoma (CTCL). PATIENTS AND METHODS: In this phase II study, patients with CTCL who had already failed three or more systemic therapies were recruited. We investigated the response rate, safety and tolerability of oral forodesine treatment in subjects with cutaneous manifestations of CTCL, stages IB, IIA, IIB, III and IVA. The safety population encompassing all stages was used for analysis of accountability, demographics and safety. The efficacy population differed from the safety population by exclusion of stage IB and IIA patients. RESULTS: All 144 patients had performance status 0-2. The median duration of CTCL from diagnosis was 53 months (5-516 months). The median number of pretreatments was 4 (range: 3-15). No complete remissions were observed. In the efficacy group of patients, 11% achieved partial remission and 50% had stable disease. The median time to response was 56 days and the median duration of response was 191 days. A total of 96% of all treated patients reported one or more adverse events (AEs) and 33% reported a serious AE. The majority of AEs were classified as mild or moderate in severity. The most commonly reported AEs (>10%) were peripheral edema, fatigue, insomnia, pruritus, diarrhea, headache and nausea. Overall eight patients died during the study: five due to sepsis and infections, one due to a second malignancy (esophageal cancer), one due to disease progression and one due to liver failure. CONCLUSION: Oral forodesine at a dose of 200 mg daily is feasible and shows partial efficacy in this highly selected CTCL population and some durable responses.

Phase I study of BCX1777 (forodesine) in patients with relapsed or refractory peripheral T/natural killer-cell malignancies.

BCX1777 (forodesine), a novel purine nucleoside phosphorylase inhibitor, induces apoptosis, mainly in T cells. To evaluate the safety, tolerability, and pharmacokinetics of BCX1777, we conducted a phase I study in patients with relapsed or refractory peripheral T/natural killer-cell malignancies. Eligible patients had relapsed or refractory peripheral T/natural killer-cell malignancies without any major organ dysfunction. BCX1777 was administered orally once daily (dose escalation: 100, 200, and 300 mg) until disease progression requiring new therapy or unacceptable adverse events occurred. A total of 13 patients were enrolled and treated in three dose cohorts (100 mg/day, five patients; 200 mg/day, three patients; 300 mg/day, five patients). Although none of the patients developed dose-limiting toxicities, further dose escalation was not performed based on data from overseas. Therefore, the maximum tolerated dose was not determined. Adverse events of grade 3 or greater (≥2 patients) included lymphopenia (62%), anemia (15%), leukopenia (8%), and pyrexia (8%). Plasma pharmacokinetics parameter of BCX1777 (area under the plasma concentration-time curve) at day 1 in each cohort was 1948 ± 884, 4608 ± 1030, and 4596 ± 939 ng•h/mL, respectively. Disease control was achieved in approximately half of patients. One patient with anaplastic large cell lymphoma, which was negative for anaplastic lymphoma kinase, achieved a complete response, and two patients with cutaneous T-cell lymphoma achieved partial responses. BCX1777 was well tolerated at doses up to 300 mg once daily and showed preliminary evidence of activity in relapsed or refractory peripheral T/natural killer-cell malignancies, warranting further investigation.

A spicamycin derivative (KRN5500) provides neuropathic pain relief in patients with advanced cancer: a placebo-controlled, proof-of-concept trial.

CONTEXT: Neuropathic pain in patients with cancer can be difficult to treat effectively. OBJECTIVES: The purpose of the study was to determine safety and efficacy of KRN5500, a novel, spicamycin-derived, nonopioid analgesic agent, in patients with advanced cancer and neuropathic pain of any etiology. METHODS: The study was a Phase 2a, multicenter, double-blind, placebo-controlled, dose escalation clinical trial. Patients with refractory neuropathic pain and advanced cancer were randomly assigned 2:1 to receive a maximum of eight single escalating doses of KRN5500 or placebo, ranging from 0.6 to 2.2 mg/m(2). The primary objective was safety and tolerability. The secondary objective was efficacy, measured by change in average pain intensity on a 0-10 numeric rating scale administered one week after the patient's final dose. RESULTS: Nineteen patients received treatment (KRN5500 n=12; placebo n=7). The most frequently reported adverse events were gastrointestinal symptoms, which were more frequent and severe with KRN5500 than placebo; two (17%) KRN5500 patients discontinued the study because of nausea and vomiting. At study endpoint, KRN5500 exhibited a significant median decrease in pain intensity from baseline of 24% compared with 0% for placebo (P=0.03). The median for largest weekly reduction in target pain intensity was 29.5% for KRN5500 and 0% for placebo patients (P=0.02). CONCLUSION: This proof-of-concept study for KRN5500 in patients with advanced cancer and any type of neuropathic pain found gastrointestinal adverse events to be the predominant safety concern. The results also provided the first indication of clinical and statistical efficacy in reducing pain intensity.

Evaluation of mitochondrial toxicity in Marmota himalayana treated with metacavir, a novel 2',3'-dideoxyguanosine prodrug for treatment of hepatitis B Virus.

Metacavir (PNA) is a novel synthetic nucleoside analogue for the treatment of hepatitis B virus (HBV). Our recent studies showed that PNA, a prodrug of 2',3'-dideoxyguanosine (ddG), exhibited lower mitochondrial toxicity in long-term cultures of HepG2 cells. In the current study, we examined the long-term effects of PNA on mitochondrial toxicity in Marmota himalayana (Himalayan marmot). Himalayan marmots were treated daily with oral PNA (50 or 100 mg/kg), ziduvidine (AZT) (100 mg/kg), or water (control) for 90 days. PNA treatment did not alter the body weight or plasma lactate acid level. In livers from the animals treated with PNA at 100 mg/kg/day, histopathology showed mild steatosis or small focal liver cell necrosis. Electron microscopy also showed minor proliferation and partial mitochondrial swelling with crista reduction. Measurement of respiratory chain complex enzyme activity and mitochondrial DNA (mtDNA) content revealed no significant differences in skeletal muscle, liver, and kidney tissues between animals treated with PNA and controls. In contrast, in Himalayan marmots treated with AZT we observed delayed toxicity, including lactic acidosis, severe hepatic steatosis, obvious mitochondrial damage, and significant decreases in respiratory chain complex enzyme activity and mtDNA content. This is similar to the delayed toxicity syndrome observed previously in animals and humans. In summary, PNA treatment did not alter mitochondrial enzyme activity or mtDNA content. This suggests that PNA could pose a very low risk for adverse mitochondrion-related effects. However, long-term hepatotoxic effects of PNA were observed, and this indicates a need for continued monitoring of PNA-associated hepatotoxicity in clinical trials.

[Oral cladribine for relapsing-remitting multiple sclerosis: another purine analogue or a genuine therapeutic innovation?]. / Cladribin-Tabletten bei schubförmiger Multipler Sklerose: Noch ein Purinanalogon oder echte therapeutische Innovation?

Azathioprine (AZA) is a purine analogue which has been used in the treatment of multiple sclerosis (MS) for over 30 years. After the approval of immunomodulatory drugs, such as recombinant interferon beta and glatiramer acetate, AZA now only plays a minor role in MS therapy. The results of a recently published phase III trial (CLARITY trial) involving an oral formulation of the purine analogue cladribine, a substance which is at least structurally related to AZA, may soon lead to the approval of cladribine tablets as a new oral MS therapeutic. The following overview provides a comparison of the mode of action, side-effect profile and data currently available on AZA and cladribine in the treatment of MS.

Antiviral activity and tolerability of amdoxovir with zidovudine in a randomized double-blind placebo-controlled study in HIV-1-infected individuals.

BACKGROUND: Amdoxovir acts synergistically with zidovudine in vitro and the combination prevents or delays the selection of thymidine analogue and K65R mutations. In silico studies have shown that a reduced dose of zidovudine (200 mg) results in decreased zidovudine-monophosphate levels, associated with toxicity, while maintaining zidovudine-triphosphate levels, which are associated with antiviral effects. Here, we aimed to assess the short-term tolerability and antiviral activity of amdoxovir in combination with reduced and standard doses of zidovudine. METHODS: The study was a double-blind, placebo-controlled study in HIV-1-infected patients not receiving antiretroviral therapy and with plasma HIV-1 RNA > or =5,000 copies/ml. Patients were randomized to 10 days of twice-daily treatment with 200 mg zidovudine, 300 mg zidovudine, 500 mg amdoxovir, 500 mg amdoxovir plus 200 mg zidovudine or 500 mg amdoxovir plus 300 mg zidovudine. The mean change in viral load (VL) log(10) and area under the virus depletion curve (AUC(VL)) from baseline to day 10 were determined. Laboratory and clinical safety monitoring were performed. RESULTS: Twenty-four patients were enrolled. The mean VL log(10) change was 0.10 with placebo, -0.69 with zidovudine 200 mg, -0.55 with zidovudine 300 mg, -1.09 with amdoxovir, -2.00 with amdoxovir plus zidovudine (200 mg) and -1.69 with amdoxovir plus zidovudine (300 mg). Amdoxovir plus zidovudine (200 mg) was significantly more potent than amdoxovir monotherapy in AUC(VL) and mean VL decline (P=0.019 and P=0.021, respectively), suggesting synergy. There was markedly decreased VL variability with the combination compared with amdoxovir alone. All adverse events were mild to moderate. CONCLUSION: The combination of amdoxovir plus zidovudine appeared synergistic with reduced VL variability. This combined therapy, including the use of a lower zidovudine dosage, warrants further development for the therapy of HIV infection.

Activation of adenosine 2A receptors preserves structure and function of podocytes.

Adenosine 2A receptor (A(2A)R) activation was recently shown to be renoprotective in diabetic nephropathy. A(2A)R are found in glomeruli and have been shown to associate with the podocyte cytoskeletal protein alpha-actinin-4, but the effect of their activation on podocyte structure and function is unknown. Podocyte injury was induced in C57BL/6 mice with puromycin aminonucleoside, and the selective A(2A)R agonist ATL313 was found to attenuate the resulting albuminuria and foot process fusion. The selective A(2A)R antagonist ZM241385 reversed the effects of ATL313. In vitro, A(2A)R mRNA and protein were expressed in a conditionally immortalized podocyte cell line, and A(2A)R-like immunoreactivity co-localized with the actin cytoskeleton. Treatment with ATL313 also blocked the increased podocyte permeability to albumin and disruption of the actin cytoskeleton that accompanied puromycin aminonucleoside-induced injury in vitro. ATL313 was ineffective, however, in the presence of the A(2A)R antagonist and in A(2A)R-deficient podocytes. It was concluded that A(2A)R activation reduces glomerular proteinuria, at least in part, by preserving the normal structure of podocyte foot processes, slit diaphragms, and actin cytoskeleton.

Nelarabine: a novel purine antimetabolite antineoplastic agent.

BACKGROUND: Nelarabine was approved by the US Food and Drug Administration (FDA) in October 2005 for the treatment of T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) that has not responded to or has relapsed after treatment with at least 2 chemotherapy regimens. OBJECTIVES: This article reviews the pharmacology, mechanism of action, and pharmacokinetic and pharmacodynamic properties of nelarabine. Also reviewed are nelarabine's clinical efficacy in T-ALL, T-LBL, and other hematologic malignancies; its toxicity profile, dosage, and administration; and areas of ongoing and future research. METHODS: Relevant literature was identified through searches of MEDLINE (1966-April 2007), International Pharmaceutical Abstracts (1970-April 2007), and the American Society of Hematology database (2003-2006) using the terms nelarabine, Arranon, 506U78, and 2-amino-6-methoxypurine arabinoside. The reference lists of the identified articles were searched for additional sources. Product information obtained from the manufacturer of nelarabine was consulted, as were the FDA reviews of nelarabine. All identified publications were considered, and those meeting the objectives of this review were included. RESULTS: Nelarabine, a soluble prodrug of 9-beta-D- arabinofuranosylguanine (ara-G), is a novel purine antimetabolite antineoplastic that preferentially accumulates in T-cells. Ara-G is rapidly phosphorylated in T-cells to ara-G triphosphate (ara-GTP), which exerts cytotoxic effects. Renal elimination of ara-G is decreased in patients with mild to moderate renal impairment; however, no dose adjustment is recommended. Accumulation of ara-GTP occurs in T-cells in a dose-dependent manner, leading to preferential cytotoxicity. Nelarabine has activity in T-cell malignancies, as evaluated in 2 Phase I and 5 Phase II studies. It received accelerated approval from the FDA based on the resuits of 2 Phase II trials, one in pediatric patients (PGAA 2001) and the other in adults (CALGB 19801). In PGAA 2001, patients with T-ALL in first relapse (n = 33) had an objective response rate of 55% (16 with a complete response [CR] and 2 with a partial response [PR]), and those with T-ALL in second relapse (n = 30) had an objective response rate of 27% (7 CR and 1 PR). Among patients with central nervous system-positive T-ALL or T-cell non-Hodgkins lymphoma (T-NHL) (n = 21), 33% had an objective response (5 CR and 2 PR); among patients with T-ALL or T-NHL with extramedullary relapse (n = 22), 14% had a PR. CALGB 19801 included 39 adult patients with T-cell malignancies, of whom 7 (18%) had a CR and an additional 2 (5%) had a CR without full hematologic recovery. The recommended dose of nelarabine in adults is 1500 mg/m(2) IV given over 2 hours on days 1, 3, and 5, repeated every 21 days; the recommended dose in pediatric patients is 650 mg/m(2) IV given over 1 hour for 5 consecutive days, repeated every 21 days. Dose-limiting toxicities observed in the Phase I and II trials included central and peripheral neurotoxicity. Symptoms of central neurotoxicity included somnolence, seizures, dizziness, confusion, and ataxia; symptoms of peripheral neurotoxicity included paresthesias, pain in the extremities, and peripheral neuropathy. CONCLUSIONS: Nelarabine is indicated for the treatment of T-ALL and T-LBL that has not responded to or has relapsed after treatment with at least 2 chemotherapy regimens. Objective response rates in Phase II clinical trials of nelarabine have ranged from 11% to 60%. Use of nelarabine is limited by potentially severe neurotoxicity.

Amdoxovir versus placebo with enfuvirtide plus optimized background therapy for HIV-1-infected subjects failing current therapy (AACTG A5118).

BACKGROUND: Amdoxovir (2,6-diaminopurine dioxolane; DAPD) is a nucleoside reverse transcriptase inhibitor (NRTI) of human immunodeficiency virus-1 (HIV-1) with activity against wild-type and NRTI-resistant viruses. METHODS: ACTG A5118 assessed the antiretroviral activity and safety of DAPD (300 mg orally, twice daily) versus placebo in combination with enfuvirtide (ENF) plus an optimized background (OB) regimen in subjects with failure of two or more antiretroviral (ARV) regimens. The primary endpoints for comparison were time-averaged area under the curve minus baseline (AAUCMB) of plasma HIV-1 RNA concentration at 24 weeks and time to first serious (DAIDS toxicity table Grade > or = 3) adverse event (AE). An unplanned interim review recommended closing enrollment because the study was unlikely to demonstrate a difference between arms. The 18 subjects on study, nine in each arm, were unblinded and allowed to continue study treatment through 48 weeks. RESULTS: Intention-to-treat analysis showed the median AAUCMB was -0.9 log10 copies/mL (95% CI = -2.2, -.0.1) in the DAPD arm and -0.9 log10 copies/ml (95% CI = -1.1, -0.1) in the placebo arm (P = 0.69). Median CD4+ T-cell increase was 79 cells/mm3 (95% CI =1, 115) in the DAPD arm and 60 (95% CI =1, 101) in the placebo arm (P = 0.45). Time to first serious AE did not differ between arms (P = 0.91). Mild decreases of creatinine clearance were observed with similar frequency between arms; no subject developed lens opacities. CONCLUSIONS: Addition of DAPD to ENF plus OB in advanced subjects with highly resistant virus appeared safe, but did not add statistically significant antiretroviral activity at 24 weeks in this small study.

[Spicamycin derivative].

Spicamycin, induced differentiation of human myeloid leukemia cells (HL-60), is found to show a potent antitumor activity by inhibiting protein synthesis. Among the various semisynthetic derivatives of spicamycin, KRN5500 showed a marked efficacy in human tumor xenograft model. KRN5500 itself has, however, only minor inhibitory effects on protein synthesis in cell free system. A metabolite, SAN-Gly, which is thought to be generated through metabolism of KRN5500 by a cytosomal enzyme, exhibited a marked inhibitory effect. KRN5500 is expected to be useful even for treatment of refractory solid tumors because of its unique antitumor mechanism. A phase I clinical trials underwent at the National Cancer Center Hospital in Tokyo and at the National Cancer Institute in the USA. Unfortunately, the drug toxicities in addition to grade 4 pulmonary disorders were occurred, partly caused by the organic solvents and chemical essential for its dissolution. To overcome such a severe adverse effects, we conducted to examine whether incorporation of KRN5500 into polymeric micelles (KRN/m) could reduce a pulmonary disorder using a bleomycin (BLM)-induced lung injury rat model or exhibit antitumor activity similar to KRN5500. In conclusion, this study demonstrated that KRN/m is superior to KRN5500 because the pulmonary toxicity was reduced and the potent antitumor activity of KRN5500 was retained after the incorporation of KRN5500 into micelles. We think that these results justify a clinical phase I trial of KRN/m.

Transformation and progression of Waldenström's macroglobulinemia following cladribine therapy in two cases: natural evolution or iatrogenic causation?

We report two cases of Waldenström's macroglobulinemia with an unusual aggressive transformation following treatment with cladribine (2-chlorodeoxyadenosine, 2-CdA), a purine analogue. The first patient developed transformation to a diffuse large-cell non-Hodgkin lymphoma, while the second developed extensive extramedullary involvement. Both patients displayed rapid progression following transformation and were refractory to chemotherapy. Both patients were pretreated with multiple courses of prednisone and chlorambucil, and transformation occurred shortly after therapy with cladribine. We propose that immune suppression from alkylating agents and purine analogues may have contributed to the unusual progression, resulting in a dismal outcome.

Short-term safety and pharmacodynamics of amdoxovir in HIV-infected patients.

OBJECTIVES: To evaluate the pharmacodynamics and safety of escalating doses of amdoxovir (DAPD) monotherapy administered to treatment-naive and experienced HIV-1-infected patients over 15 days. DESIGN: Ninety patients with plasma HIV-1 RNA levels between 5000 and 250,000 copies/ml were randomized to DAPD 25, 100, 200, 300 or 500 mg twice daily or 600 mg once daily monotherapy [antiretroviral therapy (ART)-naive and ART-experienced] or to add DAPD 300 or 500 mg twice daily to existing ART. After 15 days of dosing, patients were followed for an additional 7 days. METHODS: Antiviral activity was compared between treatment arms using log10 HIV-1 RNA based on average area under the curve minus baseline to day 15. Safety and tolerability was analyzed by incidence of grade 1 to 4 clinical and laboratory adverse events. RESULTS: In ART-naive patients receiving short-term DAPD monotherapy, a median reduction in plasma HIV-1 RNA of 1.5 log10 copies/ml at the highest doses was observed. In ART-experienced patients, the reduction in viral load observed at each dose was less than that observed in treatment-naive patients (reduction of 0.7 log10 at 500 mg twice daily). The incidence of adverse events was similar across groups with the majority of adverse events reported as mild or moderate in severity. Steady-state plasma concentrations of DAPD and dioxolane guanosine followed linear kinetics. CONCLUSIONS: DAPD was well tolerated and produced antiviral activity in treatment-naive and in some treatment-experienced patients. In ART-experienced patients, the antiviral activity was significant in those with no thymidine-analogue mutations and higher baseline CD4+ cell counts.

Purine nucleoside analogues for the treatment of hematological malignancies: pharmacology and clinical applications.

The purine nucleoside analogues (PNAs), fludarabine (FA), 2-CdA (2-chlorodeoxyadenosine, 2-CdA) and pentostatin (2'-deoxycoformycin, DCF) represent a group of cytotoxic agents with high activity in lymphoid and myeloid malignancies. PNAs share similar chemical structure and mechanism of action. Several mechanisms could be responsible for their cytotoxicity both in proliferating and quiescent cells, such as inhibition of DNA synthesis, inhibition of DNA repair and accumulation of DNA strand breaks. Induction of apoptosis through the mitochondrial pathway, direct binding to apoptosome or modulation of p53 expression all lead to apoptosis, which is the main end-point of PNA action. However, individual PNAs exhibit significant differences, especially in their interaction with enzymes involved in adenosine and deoxyadenosine metabolism. Synergistic interactions between PNAs and other cytotoxic agents (alkylating agents, anthracycline antitumor antibiotics, cytarabine, monoclonal antibodies) have been demonstrated in both preclinical and clinical studies. PNAs are highly effective in chronic lymphoid leukemias and low grade B- and T-cell non-Hodgkin's lymphomas, including Waldenström's macroglobulinemia. DCF and 2-CdA are currently the drugs of choice in hairy cell leukemia. Moreover, clinical studies have confirmed the efficacy of PNAs alone or in combination protocols in the treatment of acute myeloid leukemia and myelodysplastic syndromes. Finally, PNAs, especially FA, play an important role in non-myeloablative conditioning regimens for allogenic stem cell transplantation in high-risk patients. The toxicity profiles of PNAs are similar for all agents and consist mainly of dose-limiting myelotoxicity and prolonged immunosuppression. Three other compounds: clofarabine, nelarabine and immucillin-H are currently being evaluated clinically.

New nucleoside analogs in the treatment of hematological disorders.

Cytotoxic nucleoside analogs have a broad clinical use. They were among the first chemotherapeutic agents used in the treatment of malignant diseases. The anticancer nucleosides include analogs of physiologic pyrimidine and purine nucleosides. They are used in oncology in the treatment of both, solid tumors and hematological malignancies. These agents have many intracellular targets, e.g. they act as antimetabolites, competing with natural nucleosides during DNA or RNA synthesis and as inhibitors of key cell enzymes. Understanding of the mechanisms of action of these compounds and synthesis of new analogs provides the possibility to further expand the spectrum of their clinical use and enhance their antitumor activity. In this paper we describe mechanisms of action and possible clinical use in the treatment of hematological malignancies of these nucleoside analogs, which are now in different stages of clinical trials, namely tezacitabine, troxacitabine, clofarabine, nelarabine, decitabine, CNDAC and ECyD.

Drug-induced pulmonary infection.

Immunosuppressive drugs lead to an enhanced risk for infection. The impact of these drugs on the immune system can be broad (eg, corticosteroids) or targeted (eg, rituximab). Infections can have serious consequences, particularly if there is a delay in diagnosis. It is hoped that a knowledge of the type of immune defects that are induced by these drugs and the specific infections that have been reported will guide clinicians in the appropriate use of prophylactic regimens and diagnostic considerations in the event of pneumonia.