Biomedical subjects

Francis J Giles

Publications and source records attributed to Francis J Giles.

At least 55 records · Page 3Linked to original sources

PubMed2005

New agents in myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic disorders characterized by ineffective hematopoiesis resulting in peripheral cytopenia and by increased progression to acute myeloid leukemia (AML). Therapeutic interventions for MDS other than allogeneic stem cell transplantation have been palliative. Novel and targeted therapeutic agents such as the inhibition of farnesyl transferases and receptor tyrosine kinases, more potent thalidomide analogs, arsenic trioxide, immunomodulating agents, hypomethylating agents, and histone deacetylase inhibitors have shown encouraging results and may offer durable benefit to patients with MDS. Further development of rational therapies and improvements in the outcome of patients with MDS are likely to emerge from an increased understanding of the pathophysiology of these diseases.

Alkyl and Aryl Transferases↗

PubMed2004

Results of a phase 1-2 study of clofarabine in combination with cytarabine (ara-C) in relapsed and refractory acute leukemias.

Clofarabine (2-chloro-2'-fluoro-deoxy-9-beta-D-arabinofuranosyladenine) is a second-generation nucleoside analog with activity in acute leukemias. As clofarabine is a potent inhibitor of ribonucleotide reductase (RnR), we hypothesized that clofarabine will modulate ara-c triphosphate accumulation and increase the antileukemic activity of cytarabine (ara-C). We conducted a phase 1-2 study of clofarabine plus ara-C in 32 patients with relapsed acute leukemia (25 acute myeloid leukemia [AML], 2 acute lymphoblastic leukemia [ALL]), 4 high-risk myelodysplastic syndrome (MDS), and 1 blast-phase chronic myeloid leukemia (CML).(1) Clofarabine was given as a 1-hour intravenous infusion for 5 days (days 2 through 6) followed 4 hours later by ara-C at 1 g/m(2) per day as a 2-hour intravenous infusion for 5 days (days 1 through 5). The phase 2 dose of clofarabine was 40 mg/m(2) per day for 5 days. Among all patients, 7 (22%) achieved complete remission (CR), and 5 (16%) achieved CR with incomplete platelet recovery (CRp), for an overall response rate of 38%. No responses occurred in 3 patients with ALL and CML. One patient (3%) died during induction. Adverse events were mainly less than or equal to grade 2, including transient liver test abnormalities, nausea/vomiting, diarrhea, skin rashes, mucositis, and palmoplantar erythrodysesthesias. Plasma clofarabine levels generated clofarabine triphosphate accumulation, which resulted in an increase in ara-CTP in the leukemic blasts. The combination of clofarabine with ara-C is safe and active. Cellular pharmacology data support the biochemical modulation strategy.

Acute Disease↗

PubMed2004

The spermatozoa protein, SLLP1, is a novel cancer-testis antigen in hematologic malignancies.

PURPOSE: Neoplastic cells often aberrantly express normal testicular proteins. Because these proteins have a very restricted normal tissue expression, they may be suitable targets for immunotherapy. SLLP1 is an intra-acrosomal, nonbacteriolytic, c lysozyme-like protein recently isolated from human spermatozoa. In this study, we determined whether SLLP1 is a novel cancer-testis antigen in hematologic malignancies EXPERIMENTAL DESIGN: SLLP1 expression in hematologic tumor cells and normal tissues was determined using a combination of reverse transcription-PCR, real-time PCR, and Western blot analysis. The presence of antibodies against SLLP1 was determined by ELISA analysis. RESULTS: SLLP1 was aberrantly expressed in the tumor cells from 2 of 9 acute myeloid leukemia, 3 of 11 chronic lymphocytic leukemia, 4 of 14 chronic myeloid leukemia, and 6 of 17 multiple myeloma. In contrast, they were not detected in corresponding specimens from any healthy donors. SLLP1 exhibited a very restricted normal tissue expression, being found only in testis/spermatozoa. SLLP1 was expressed in some tumor cells at a level of >25%. High titer IgG antibodies against SLLP1 were also detected in the sera of some of these patients. CONCLUSIONS: SLLP1 is a novel cancer-testis antigen in hematologic malignancies and is capable of eliciting B-cell immune responses in vivo in cancer-bearing individuals. Our results, therefore, support SLLP1 as a protein target appropriate for additional in vitro study to define its suitability for immunotherapy.

Antigens, Neoplasm↗

PubMed2004

Free circulating soluble CD52 as a tumor marker in chronic lymphocytic leukemia and its implication in therapy with anti-CD52 antibodies.

BACKGROUND: The CD52 antigen is a glycoprotein anchored on the cell membrane of mature B and T lymphocytes, monocytes, and eosinophils. Alemtuzumab (CAMPATH-1H; anti-CD52) is currently approved for the treatment of patients with refractory chronic lymphocytic leukemia (CLL). The authors investigated the possibility that CD52 may be shed from cells and, once soluble, may bind to injected alemtuzumab, forming immune complexes. METHODS: The authors used Western blot analysis, immunoprecipitation, and enzyme-linked immunoadsorbent assay to investigate the presence of soluble CD52 (sCD52) in the plasma specimens of 117 patients with CLL. They also used in vitro mixing experiments to examine the ability of sCD52 to compete with cells and sequester therapeutic alemtuzumab. RESULTS: The authors detected high levels of sCD52 in the plasma specimens of patients with CLL. sCD52 can compete with cells in vitro for binding to alemtuzumab, and can form complexes in patients receiving alemtuzumab. Plasma levels of sCD52 were found to be correlated (r)with Rai stage (P = 0.0001), beta-2-microglobulin (beta-2M) levels (P = 0.00002), soluble CD23 levels (r = 0.42, P < 0.001), and immunoglobulin mutation status (P = 0.003). In the multivariate analysis adjusted for beta-2M level, patients with sCD52 levels > 2336 nM/L had a nearly 4-fold increase in risk of death. Higher levels of plasma alemtuzumab were achieved when levels of sCD52 were lower. CONCLUSIONS: These data not only demonstrated that sCD52 was detectable and useful in the staging and monitoring of patients with CLL, but also showed that sCD52 formed immune complexes with alemtuzumab and may influence the efficacy and toxicity of alemtuzumab therapy.

Adult↗

PubMed2004

Fludarabine and mitoxantrone for patients with chronic lymphocytic leukemia.

BACKGROUND: The objective of the current study was to assess the efficacy of combination therapy with fludarabine and mitoxantrone in patients with B-cell chronic lymphocytic leukemia (CLL). METHODS: Eighty-eight patients were treated with fludarabine 30 mg/m(2) intravenously daily for 3 days and mitoxantrone 10 mg/m(2) on Day 1 (FN). Patients were divided into four groups based on expected response to single-agent fludarabine. These four groups included previously untreated patients, patients who previously were treated with alkylating agents, patients who were successfully treated with alkylating agents and fludarabine but who developed recurrent disease, and patients whose disease was refractory to fludarabine with or without alkylating agents. RESULTS: The overall response rate was 66%. The response rates were 83% in previously untreated patients, 87% in patients previously treated with alkylating agents, 50% in patients whose disease was not refractory to fludarabine at the start of therapy, and 25% in patients whose disease was refractory to fludarabine. The complete remission (CR) rate was 20% for previously untreated patients, which was not significantly different from the CR rate for a group of historical control patients who were treated with single-agent fludarabine. The median follow-up was 8 years for surviving patients. The median progression free survival was 24 months for all patients and 34 months for previously untreated patients. The median overall survival was 40 months, and the median survival of previously untreated patients was 88 months. The most common toxicities were myelosuppression and infection. Eleven patients (12.5%) developed a second malignancy after a median of 62 months. CONCLUSIONS: The FN regimen did not have a significant advantage over fludarabine alone in the treatment of patients with CLL.

Adult↗

PubMed2004

Outcome with the hyper-CVAD regimens in lymphoblastic lymphoma.

Therapy of lymphoblastic lymphoma (LL) has evolved with use of chemotherapy regimens modeled after those for acute lymphocytic leukemia (ALL). We treated 33 patients with LL with the intensive chemotherapy regimens hyper-CVAD (fractionated cyclophosphamide, vincristine, Adriamycin, and dexamethasone) or modified hyper-CVAD used for ALL at our institution. Induction consolidation was administered with 8 or 9 alternating cycles of chemotherapy over 5 to 6 months with intrathecal chemotherapy prophylaxis, followed by maintenance therapy. Consolidative radiation therapy was given to patients with mediastinal disease at presentation. No consolidation with autologous or allogeneic stem cell transplantation was performed. At diagnosis, 80% were T-cell immunophenotype, 70% were stages III to IV, 70% had mediastinal involvement, and 9% had central nervous system (CNS) disease. Of the patients, 30 (91%) achieved complete remission, and 3 (9%) achieved partial response. Within a median of 13 months, 10 patients (30%) relapsed or progressed. Estimates for 3-year progression-free and overall survival for the 33 patients were 66% and 70%, respectively. Estimates for the patients with known T-cell immunophenotype were 62% and 67%, respectively. No parameters (eg, age, stage, serum lactate dehydrogenase [LDH], beta(2) microglobulin) appeared to influence outcome except for CNS disease at presentation. Modification of the hyper-CVAD regimen with anthracycline intensification did not improve outcome. Other modifications of the program could include incorporation of monoclonal antibodies and/or nucleoside analogs, particularly for slow responders or those with residual mediastinal disease.

Adolescent↗

PubMed2004

The clinical significance of large cells in bone marrow in patients with chronic lymphocytic leukemia.

BACKGROUND: Patients with chronic lymphocytic leukemia (CLL) that transforms to Richter syndrome (RS) frequently show atypical lymphocytes in bone marrow; however, a diagnosis of RS requires confirmation of the presence of sheets of large cells in bone marrow or lymph nodes. METHODS: In this study, the authors evaluated the clinical significance of scattered large cells in bone marrow. They assessed the possibility of predicting transformation to RS in bone marrow smears by counting the percentages of prolymphocytes and large cells in 78 patients with CLL and 29 patients with lymph node biopsy-confirmed RS. RESULTS: The percentage of large cells was found to be correlated with decreasing survival in a continuous fashion (P = 0.006). It is interesting to note that patients who had > 7% large cells in the bone marrow and elevated beta(2)-microglobulin (beta(2)-M) levels (> 5 mg/L) had a survival duration identical to that of patients with RS, and these factors together were a strong predictor of RS (P < 0.001). CONCLUSIONS: Patients with CLL who had bone marrow that contained > 7% large cells and who had beta(2)-M levels > 5 mg/L had a disease that was similar to RS, and the combination of large cells and beta(2)-M can be used as a surrogate marker for RS.

Adult↗

PubMed2004

Soluble vascular endothelial growth factor receptor 1, and not receptor 2, is an independent prognostic factor in acute myeloid leukemia and myelodysplastic syndromes.

BACKGROUND: Vascular endothelial growth factor (VEGF) and its receptors (VEGFRs) are major regulators of angiogenesis, which plays a key role in the growth and dissemination of solid tumors and hematologic neoplasms. METHODS: The authors measured the plasma concentrations of soluble VEGFR1 (sVEGFR1) and sVEGFR2 in 133 patients with acute myeloid leukemia (AML) and in 80 patients with myelodysplastic syndromes (MDS) at the time of initial presentation and compared clinical behaviors. RESULTS: A reverse correlation was observed between plasma sVEGFR1 levels and the rate of complete remission (CR) in patients with AML, but not in patients with MDS. In contrast, increased plasma levels of sVEGFR2 were correlated with a lower CR rate in patients with MDS, but not in patients with AML. Cox regression model analysis demonstrated that plasma levels of sVEGFR1, but not sVEGFR2, were independent prognostic factors in both patients with AML and patients with MDS. CONCLUSIONS: The findings suggest that different mechanisms are involved in the pathophysiology of AML and MDS. The concentration of sVEGFR1 and sVEGFR2 in plasma should be considered a significant factor in guiding antiangiogenic therapy for AML and MDS. They may play a role in the pharmacodynamics of therapeutic agents that are supposed to bind directly to these receptors.

Adolescent↗

PubMed2004

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.

Acute Disease↗

PubMed2004

Phase II study of R115777, a farnesyl transferase inhibitor, in myelodysplastic syndrome.

PURPOSE: To perform a phase II study of the farnesyl transferase inhibitor R115777 (Zarnestra; Johnson and Johnson Pharmaceutical Research and Development, Raritan, NJ) in patients with myelodysplastic syndrome (MDS), using doses recommended in a phase I study in relapsed/refractory leukemia. PATIENTS AND METHODS: Patients with MDS were treated with R115777 at doses of 600 mg orally (PO) bid in cycles of 4 weeks of therapy followed by a 2-week rest period. Dose reduction rules for toxicity were applied. RESULTS: Twenty-seven of the 28 patients treated were assessable. Three patients responded (complete remission, n = 2; partial remission, n = 1). Responders included two patients with refractory anemia with excess blasts and one patient with refractory anemia with excess blasts in transformation. Two of the responders had a diploid karyotype and one had multiple cytogenetic abnormalities including monosomy 5 and 7. The starting dose of 600 mg PO bid resulted in side effects (myelosuppression, fatigue, neurotoxicity, rash, or leg pain) necessitating dose reduction (n = 4) or discontinuation of therapy (n = 7) in 11 (41%) of 27 patients during the induction period (12 weeks). Lower doses of 300 mg PO bid were well tolerated. All responses occurred in patients who had been reduced to this dose level during the initial two cycles. CONCLUSION: This study suggests that R115777 has modest activity in MDS patients, but that, in this patient population, 4 weeks of daily doses of 600 mg PO bid is not tolerated. Further exploration of the optimal dose/schedule and correlation with biologic end points are warranted.

Aged↗

PubMed2004

Mammalian target of rapamycin inhibition as therapy for hematologic malignancies.

The mammalian target of rapamycin (mTOR) is a downstream effector of the phosphatidylinositol 3-kinase (PI3K)/Akt (protein kinase B) signaling pathway, which mediates cell survival and proliferation. mTOR regulates essential signal-transduction pathways, is involved in the coupling of growth stimuli with cell cycle progression, and initiates mRNA translation in response to favorable nutrient environments. mTOR is involved in regulating many aspects of cell growth, including membrane traffic, protein degradation, protein kinase C signaling, ribosome biogenesis, and transcription. Because mTOR activates both the 40S ribosomal protein S6 kinase (p70s6k) and the eukaryotic initiation factor 4E-binding protein 1, its inhibitors cause G1-phase cell cycle arrest. Inhibitors of mTOR also prevent cyclin dependent kinase (CDK) activation, inhibit retinoblastoma protein phosphorylation, and accelerate the turnover of cyclin D1, leading to a deficiency of active CDK4/cyclin D1 complexes, all of which may help cause G1-phase arrest. It is known that the phosphatase and tensin homologue tumor suppressor gene (PTEN) plays a major role in embryonic development, cell migration, and apoptosis. Malignancies with PTEN mutations, which are associated with constitutive activation of the PI3K/Akt pathway, are relatively resistant to apoptosis and may be particularly sensitive to mTOR inhibitors. Rapamycin analogs with relatively favorable pharmaceutical properties, including CCI-779, RAD001, and AP23573, are under investigation in patients with hematologic malignancies.

Apoptosis↗

PubMed2004

Phase II study of SU5416, a small molecule vascular endothelial growth factor tyrosine kinase receptor inhibitor, in patients with refractory multiple myeloma.

PURPOSE: Increased bone marrow angiogenesis and vascular endothelial growth factor (VEGF) levels are of adverse prognostic significance in patients with multiple myeloma (MM). VEGF, a soluble circulating angiogenic molecule, acts via receptor tyrosine kinases, including VEGF receptor 2. SU5416 is a small molecule VEGF receptor 2 inhibitor. EXPERIMENTAL DESIGN: Adult patients with advanced MM were entered on a multicenter phase II study. RESULTS: Twenty-seven patients (median age 69, range 39-79), median 4 (0-10) lines of prior therapy, 14 with prior thalidomide therapy, received SU5416 at 145 mg/m(2) twice weekly i.v. for a median of two 4-week cycles (range 0.2-9). Grade 3/4 toxicities were rarely observed; the most frequent was thrombocytopenia (12%). Mild-to-moderate toxicities included nausea (63%), headache (56%), diarrhea, vomiting (both 37%), and fatigue (33%). There were three thromboembolic episodes and five cases of new onset hypertension. Two (7%) patients did not complete the first 4-week cycle of therapy because of adverse events (pneumonia and headache). There were no objective responses. Four patients had disease stabilization for >/==" BORDER="0">4 months. A decrease in median VEGF plasma levels was observed in patients with stable disease (n = 7) compared with patients with progressive disease (n = 5). Overall median survival was 42 weeks (range 3-92+). CONCLUSIONS: Although SU5416 had minimal clinical activity, signs of biological activity (decrease in plasma VEGF levels) suggest that angiogenic modulation may be of value in patients with MM.

Adult↗

PubMed2004

Accelerated and blastic phases of chronic myelogenous leukemia.

Chronic myelogenous leukemia (CML) may have a biphasic or triphasic course, whereby patients who were initially diagnosed in the chronic phase (CP) develop more aggressive disease, frequently pass through an intermediate or accelerated phase (AP), and finally evolve into an acute leukemia like blastic phase (BP). A slowing in the rate of development of AP or BP has accompanied successive improvements in therapy for patients who have CP CML. Variable diagnostic criteria for AP and BP are used in the literature, rendering comparisons difficult. The management of patients in AP or BP consistently has been less effective than the management of those inCP for all modalities of therapy. This article reviews the current diagnostic criteria, therapeutic strategies, outcomes, and investigational therapies for AP and BP CML.

Antineoplastic Agents↗

PubMed2004

Pilot study of etanercept in patients with relapsed cutaneous T-cell lymphomas.

BACKGROUND: Tumor necrosis factor (TNF)-alpha has been implicated in the pathogenesis of cutaneous T-cell lymphoma (CTCL). OBJECTIVE: To assess the toxicity, safety, and efficacy of etanercept (soluble TNF receptor) in patients with relapsed CTCL. METHODS: Etanercept was administered twice weekly at a dose of 25 mg subcutaneously. Patients with improvement after two months could be continued on treatment. RESULTS: Twelve out of the 13 patients enrolled on study were evaluable (Stage I-IIA, 3 patients; Stage IIB-IV disease, 9 patients). The median number of previous therapies was 7 (range, 3-12). Etanercept induced partial remission in one patient (8%) and minor response in one patient (8%), both of whom had Stage IB disease. Most patients experienced no side effects. CONCLUSION: This pilot study suggests that etanercept is safe and generally well tolerated in patients with CTCL. The effect of etanercept in a larger cohort of patients with early disease merits investigation.

Adult↗

PubMed2004

A fludarabine, topotecan, and cytarabine regimen is active in patients with refractory acute myelogenous leukemia.

As fludarabine, topotecan and cytarabine (ara-C) are effective in acute myeloid leukemia (AML), a pilot study of these three agents combined (FTA) was conducted. FTA consisted of topotecan 1.25 mg/m2 by CIV days 1-5, fludarabine 15 mg/m2 and ara-C 0.5 g/m2 IV, BID, on days 2-6. Seventeen patients (6 primary resistant, 11 relapsed) with AML received 33 courses of FTA. Six patients (35%) achieved complete remission. Seven patients (41%) developed grade 3 or 4 diarrhea. FTA was effective and warrants further study in patients with refractory AML.

Adult↗

PubMed2004

A phase III, randomized, double-blind, placebo-controlled, study of iseganan for the reduction of stomatitis in patients receiving stomatotoxic chemotherapy.

The invasion and colonization of oral cavity mucosal tissues by microflora may contribute to the pathophysiology of ulcerative oral mucositis (UOM). Iseganan is an analog of protegrin-1, a naturally occurring peptide with broad-spectrum microbicidal activity. A randomized, double-blind, placebo-controlled study was conducted to evaluate the efficacy and safety of iseganan in preventing UOM after stomatotoxic therapy. Patients received an oral rinse, consisting of iseganan 9mg or placebo, to be swished/swallowed six times daily, starting with stomatotoxic therapy and continuing up to 21 days. Patients were assessed for stomatitis and UOM, and administered a questionnaire evaluating mouth pain and difficulty swallowing thrice weekly. The primary study efficacy endpoint was the proportion of patients who did not have peak stomatitis NCI-CTC grade >or=2. Between November 2001 and June 2002, 502 patients were randomized to receive iseganan (251) or placebo (251). Equivalent numbers of patients in both cohorts received bone marrow or peripheral blood allogeneic or autologous stem cell transplantation (SCT). Forty-three percent and 37% of iseganan and placebo patients, respectively, did not have peak stomatitis grade =2 (P = 0.182). There was no significant difference between the cohorts in stomatitis severity, incidence of UOM, peak mouth pain, peak difficulty swallowing, amount of opiate analgesics used, or adverse event type or incidence. A major impact of Iseganan on reducing stomatitis, UOM, or its clinical sequelae in patients receiving stomatotoxic therapy was not detected on this study.

Antimicrobial Cationic Peptides↗

PubMed2004

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.

Adolescent↗

PubMed2004

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.

Acute Disease↗