Activity of interferon-alpha and isotretinoin in patients with advanced, refractory lymphoid malignancies

BACKGROUND: Interferon-alpha (IFN-alpha) and retinoids have shown nonoverlapping toxicity and each has shown antitumor activity in patients with lymphoma. The aim of the current study was to assess the toxicity, safety, and efficacy of IFN-alpha combined with isotretinoin in patients with advanced, refractory lymphoid malignancies. METHODS: Adults with biopsy-proven advanced lymphoid malignancy were treated. Patients with compromised bone marrow function (platelet counts as low as 30 x 10(9)/L) were eligible. Treatment was comprised of IFN-alpha at a starting daily dose of 3 mega units subcutaneously and isotretinoin orally starting at a dose of 1 mg/kg daily in 2 divided doses. RESULTS: Forty-four patients were evaluable. Their median age was 57 years (range, 18-82 years). Eighteen patients had advanced cutaneous T-cell lymphoma, 6 patients had peripheral T-cell lymphoma, 14 patients had Hodgkin disease, and 6 patients had a variety of other lymphoid malignancies. Patients with Hodgkin disease had received a median of 6 previous therapies (range, 3-12 therapies) and patients with other lymphoid malignancies had received a median of 4 previous therapies (range, 1-9 therapies). The median duration of treatment was 4 months (range, 0.25-38 months). The overall response rate was 38.6% (complete response in 5 patients [11.3%] and partial response in 12 patients [27.3%]). The median response duration was 3 months (range, 1-95+ months). The most common toxicities were low-grade fever, flu-like symptoms, and fatigue (IFN-alpha effects); dry mouth and skin and hypertriglyceridemia (cis-retinoic acid effects); and thrombocytopenia (which generally occurred in patients with low baseline platelet counts). CONCLUSIONS: IFN-alpha and isotretinoin combination therapy had antitumor activity and was well tolerated in heavily pretreated patients with lymphoid malignancies.     

Phase I and pharmacokinetic study of a low-clearance, unilamellar liposomal formulation of lurtotecan, a topoisomerase 1 inhibitor, in patients with advanced leukemia

BACKGROUND: OSI-211 is a low-clearance, unilamellar liposomal formulation of a water-soluble camptothecin analogue, lurtotecan. OSI-211 has significant activity in severe combined immunodeficient mouse models of human leukemia. METHODS: This study was conducted to define the dose-limiting toxicities (DLT) and pharmacokinetics of OSI-211 in patients with refractory myeloid leukemias. Patients with refractory acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or chronic myelogenous leukemia in blastic phase (CML-BP) were eligible. OSI-211 was given as an intravenous infusion over 30 minutes daily for 3 days. The starting dose was 1.5 mg/m2 per day (4.5 mg/m2 per course). The dose was escalated by 50% until Grade 2 toxicity was observed and then by 30-35% until the DLT was defined. Serial plasma and urine samples were collected, and drug levels were determined by high-performance liquid chromatography with fluorescence detection. RESULTS: Twenty patients (18 patients [90%] with AML, and 1 patient each [5%] with MDS and CML-BP) were treated. Mucositis and diarrhea were considered to be the DLTs. The maximum tolerated dose was 3.7 mg/m2 per day. Fourteen of 18 evaluable patients (78%) with AML or MDS achieved transient bone marrow aplasia. The mean systemic clearance of lurtotecan in plasma was 0.946 +/- 1.53 L/hour/m2. Urinary recovery of lurtotecan was 6.66% +/- 5.26% (range, 1.05-18.4%). CONCLUSIONS: Liposomal encapsulation of lurtotecan altered its metabolism significantly. There was no evident correlation between exposure, as measured by plasma pharmacokinetics of lurtotecan, and clinical response or toxicities. OSI-211 merits further study in hematologic malignancies.     

The human glutathione S-transferase P1 protein is phosphorylated and its metabolic function enhanced by the Ser/Thr protein kinases, cAMP-dependent protein kinase and protein kinase C, in glioblastoma cells

We report here that the human glutathione S-transferase P1 (GSTP1) protein, involved in phase II metabolism of many carcinogens and anticancer agents and in the regulation of c-Jun NH(2)-terminal kinase-mediated cell signaling, undergoes phosphorylation by the Ser/Thr protein kinases, cAMP-dependent protein kinase (PKA) and protein kinase C (PKC), resulting in a significant enhancement of its metabolic activity. GSTP1 phosphorylation by PKA was glutathione (GSH)-dependent, whereas phosphorylation by PKC did not require but was significantly enhanced by GSH. In the presence of GSH, the stoichiometry of phosphorylation was 0.4 +/- 0.03 and 0.53 +/- 0.02 mol incorporated phosphate per mole of dimeric GSTP1 protein. The GSTP1 protein was phosphorylated, in the presence of GSH, by eight different PKC isoforms (alpha, betaIota, betaIotaIota, delta, epsilon, gamma, eta, and zeta), belonging to the three major PKC subclasses, albeit with various efficiencies. The catalytic efficiency, k(cat)/K(m), of the phosphorylated GSTP1 was more than double that of the unphosphorylated protein. In MGR3 human glioblastoma cells, PKA and PKC activation resulted in a significant increase in the level of phosphorylation of the GSTP1 protein and was accompanied by a 2.1- and 2.7-fold increase, respectively, in specific GSTP1 activity in the cells. Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. The GSH-dependence of the phosphorylation suggests that under high intracellular GSH conditions, such as is present in most drug-resistant tumors, the GSTP1 protein will exist in a hyper-phosphorylated and enzymatically more active state. In normal cells, the functional activation of the GSTP1 protein by PKA- and PKC-dependent phosphorylation could represent a potentially important mechanism of cellular protection, whereas in tumors, increased phase II metabolism of anticancer drugs by the more active phosphorylated GSTP1 protein could contribute to the drug resistance and therapeutic failure frequently associated with increased activities of these Ser/Thr kinases.     

Clinical relevance of circulating angiogenic factors in patients with non-Hodgkin's lymphoma or Hodgkin's lymphoma

Vascular endothelial growth factor (VEGF), basic-fibroblast growth factor (bFGF), hepatocyte growth factor (HGF), and angiogenin are important angiogenic factors. In 65 patients with non-Hodgkin's lymphoma (NHL), pre-treatment VEGF, bFGF, and HGF levels were significantly elevated compared to normal individuals, while angiogenin levels were significantly subnormal. In 37 patients with Hodgkin's disease, pre-treatment levels of VEGF and HGF were significantly elevated, bFGF levels were normal, and angiogenin levels were significantly subnormal. In patients with NHL, post-therapy levels of angiogenin were independently predictive of survival. Both pre-therapy and post-therapy VEGF levels were independently predictive of survival in patients with HD.     

Telomerase activity is not a prognostic factor in chronic lymphocytic leukemia

We measured telomerase activity (TA) in bone marrow samples from 214 patients with CLL and correlated it with patients' characteristics and survival. In >50% of cases (126/214; 59%) no detectable TA was found. There was no difference in TA between previously treated (n = 153) and untreated (n = 61) patients (P = 0.4), or patients with various Rai (0-IV) stages (P = 0.85). TA correlated significantly with white blood cell and lymphocyte count (P = 0.02 and 0.01, respectively) but not with bone marrow cellularity, beta2-microglobulin (beta2M), or other patient characteristics. Patients who had no TA had slightly lower beta2M and lower lymphocyte counts (P = 0.5 and 0.04, respectively) as compared with patients with detectable TA. However, there was no correlation between TA and survival. This data suggests that TA may not play a significant role in the clinical behavior of CLL.     

Effects of SU5416, a small molecule tyrosine kinase receptor inhibitor, on FLT3 expression and phosphorylation in patients with refractory acute myeloid leukemia

Acute myeloid leukemia (AML) is associated with dysregulated hematopoietic cell proliferation and increased bone marrow angiogenesis, each regulated by signaling through receptor tyrosine kinases (RTKs). SU5416 is a small molecule inhibitor of VEGF receptors, c-kit and FLT3 and therefore provides a novel opportunity to target both angiogenesis and proliferation in AML. SU5416 was assessed in a phase II hematological malignancy trial in the US, where partial responses were observed in two of 33 patients. Since AML provides a unique platform to evaluate mechanism of action of small molecule inhibitors, investigation of the effect of SU5416 on FLT3 expression and phosphorylation in blood and bone marrow was an additional focus of this trial. Phosphorylated FLT3 was detected by immunoprecipitation/Western analysis in peripheral blood samples from 17 of 22 patients, and seven exhibited strong inhibition of phosphorylation immediately following a 1h SU5416 infusion, demonstrating that SU5416 can modulate RTK phosphorylation in humans. Although no clear correlation with clinical response was observed, analysis of patient plasma drug levels suggested that a threshold SU5416 concentration of 15 microM was associated with FLT3 inhibition. This observation was supported by data from an ex vivo model where AML cells were spiked into human blood, established to mimic the clinical setting and enable more rigorous analysis of effect of SU5416. In addition, FLT3 protein levels were downregulated in patient bone marrow samples, analyzed by an RIA assay. To identify putative predictors of response, patient plasma was analyzed for levels of secreted ligands of SU5416 targets; SCF and FLT3 ligand. Baseline levels of SCF in patients with stable or progressive disease were significantly higher than those in normal donors, whereas FLT3 ligand levels in patients who exhibited progressive disease were significantly lower than those in normal donors. The translational and clinical analyses described in this report provide some insights into the mechanism and duration of action of SU5416.     

Helicobacter pylori and gastric cancer prevention is possible

Epidemiological data gathered during the past few years have shown an association between Helicobacter pylori infection and gastric carcinoma. This association is considered to be causal because of its biological plausibility and the existence of an animal model, even though the positive consequences of eradication on cancer prevention have not yet been definitely proven. The limited proportion of H. pylori infected subjects who develop a gastric cancer can be explained by host factors (certain alleles of IL-1beta) and bacterial factors (cag positive strains), and to a lesser extent by environmental factors (diet). Arguments in favor of the prevention of gastric carcinoma by eradicating H. pylori are now stronger than before, given the availability of simple and accurate diagnostic tests (serology) and treatment follow-up (urea breath test), as well as a 7-day treatment which is usually sufficient for eradication.     

Investigational strategies in chronic myelogenous leukemia

Imatinib is the cornerstone of therapy in chronic myelogenous leukemia (CML) and a model for the development of novel agents directed at specific targets. The results of imatinib therapy continue to improve with approaches such as higher doses of imatinib and, possibly, with combinations of imatinib and interferon-alpha with or without cytarabine. There are multiple targets with agents directed to them that may prove to be synergistic with imatinib. These approaches are attractive, particularly when dealing with imatinib resistant CML, to prevent resistance and improve the probability of cure. The continued understanding of the biology of CML and mechanisms of resistance to imatinib and the ability to develop target-specific therapies should lead to the increased probability of cure for most patients who have CML.     

The 5-yr HAQ-disability is related to the first year's changes in the narrowing, rather than erosion score in patients with recent-onset rheumatoid arthritis

OBJECTIVE: To evaluate the predictive validity of radiological change on 5-yr disability in rheumatoid arthritis (RA). METHODS: The study was designed to be multicentre, prospective, longitudinal, with a 5-yr follow-up. Participants were RA patients (ACR criteria), with a disease duration of <1 yr at entry. Radiographs of the hands and feet in posteroanterior view at baseline and after 12 months of follow-up (van der Heijde's modification of Sharp method) were used for structural evaluation. Disability was evaluated with Health Assessment Questionnaire (HAQ) at yr 5. Analyses consisted of (i) correlation existing between the changes in the radiological scores during the first year and the HAQ value at yr 5 and (ii) determination of the optimal cut-off in the changes in the radiological scoring system, by ROC curve analysis, in which variable to be explained was disability status at yr 5, defined by HAQ value of at least 1. RESULTS: Due to missing data and/or lost to follow-up, 135 patients (out of the 191 recruited patients) were included in the analyses (mean change in the radiological score = 4.9 +/- 8.7 points, mean HAQ at yr 5 = 0.62 +/- 0.68). There was a statistically significant correlation between the HAQ-disability status at yr 5 and the changes observed in the radiological total damage and narrowing scores during the first year (r = 0.18, P = 0.046 and r = 0.25, P = 0.006, respectively). Conversely, the short-term changes in the erosion score were not correlated with subsequent HAQ-disability (r = 0.084, P = 0.36). A change of at least 2 points in the total X-ray score was considered as optimal (sensitivity, specificity, positive and negative predictive values of 66.7, 53.9, 32.8 and 82.8%, respectively). CONCLUSION: This work shows that early changes in joint damage in patients with recent-onset RA are related to subsequent HAQ-disability. This relationship is due to changes in narrowing, rather than in erosion score, suggesting that the joint narrowing score might be of great importance in the follow-up of RA patients and in the reports of scientific results. The weak performance of the thresholds established using predictive validity for subsequent HAQ-disability compromise their use at the individual level.