Citations

Abstract Purpose: The serine/threonine kinase inhibitor flavopiridol targets multiple cyclin-dependent kinases, induces checkpoint arrest, and interrupts transcriptional elongation. We designed a phase I clinical trial using a timed sequential therapy approach where flavopiridol was given for the dual purpose of initial cytoreduction and enhancing cell cycle progression of the remaining leukemia cell cohort followed by cycle-dependent drugs 1-β-d-arabinofuranosylcytosine (ara-C) and mitoxantrone. Experimental Design: Flavopiridol was given by 1-hour infusion daily for 3 days beginning day 1 followed by 2 g/m2/72 h ara-C beginning day 6 and 40 mg/m2 mitoxantrone beginning day 9. In vivo correlates included pharmacokinetics, modulation of blast cycle regulators, and serum and marrow supernatant vascular endothelial growth factor levels. Results: Of 34 adults receiving induction therapy, 16 (47%) evinced direct leukemia cytotoxicity with ≥50% drop in peripheral blast counts and tumor lysis in 9 (26%). Four (12%) died during therapy (two fungal infections and two sudden death). Dose-limiting toxicity occurred at 60 mg/m2/d with profound neutropenia >40 days duration, and maximal tolerated dose was 50 mg/m2/d. Overall response rate was 31% in 26 acute myelogenous leukemia and 12.5% in acute lymphoblastic leukemia. Pharmacokinetics showed that a linear two-compartment model with first-order elimination provided the best fit of the observed concentration versus time data. Flavopiridol down-regulated one or more target proteins in marrow blasts in vivo. Vascular endothelial growth factor was detected in sera and marrow supernatant pretreatment, and sera obtained on day 3 inhibited bovine aortic endothelial cell proliferation by a mean of 32% (range, 10-80%). Conclusions: Our data suggest that flavopiridol is cytotoxic to leukemic cells and, when followed by ara-C and mitoxantrone, exerts biological and clinical effects in patients with relapsed and refractory acute leukemias. These findings warrant continuing development of flavopiridol at 50 mg/m2/d × 3 days in combination with cytotoxic and biological agents for acute leukemias.

Abstract The ability of cancers to evade immune surveillance and resist immunotherapy raises a fundamental question of how tumor cells survive in the presence of a competent immune system. Studies to address this question have primarily focused on mechanisms by which tumor cells avoid recognition by or induce tolerance in the immune system. However, little is known about whether cancer cells also acquire an intrinsic ability to resist killing by immune effectors. We find that cancer cells enhance their ability to withstand an attack by cytotoxic immune effector cells via acquisition of specific genetic alterations that interfere with the shared mitochondrial death signaling pathway entrained by granzyme B, IFN-γ, and Apo2 ligand/tumor necrosis factor–related apoptosis inducing ligand (Apo2L/TRAIL), three key mediators of immunologic cell–mediated cytotoxicity. We show that the coexistence of specific mitochondrial signaling defects (either deletion of Bax, overexpression of Bcl-xL, or deletion of Smac) with expression of X-linked inhibitor of apoptosis protein decreases the sensitivity of cancer cells to IFN-γ/Apo2L/TRAIL– or granzyme B–induced apoptosis, lymphocyte-mediated cytotoxicity in vitro, and adoptive cellular immunotherapy in vivo. Conversely, negating X-linked inhibitor of apoptosis protein expression or function in tumor cells with defective mitochondrial signaling enables direct activation of caspase-3/-7 by granzyme B or Apo2L/TRAIL, and restores their susceptibility to immunologic cytotoxicity. These findings identify an important mechanism by which cancers evade elimination by immune effector cells and suggest that cancer immunotherapy might be improved by concurrent strategies to alleviate or circumvent the intrinsic mitochondrial death signaling defects that help cancer cells resist immunologic cytotoxicity. (Cancer Res 2006; 66(3): 1730-9)

Abstract The insulin-like growth factor receptor (IGF-IR) and insulin receptor are either overactivated and/or overexpressed in a wide range of tumor types and contribute to tumorigenicity, proliferation, metastasis, and drug resistance. Here, we show that BMS-554417, a novel small molecule developed as an inhibitor of IGF-IR, inhibits IGF-IR and insulin receptor kinase activity and proliferation in vitro, and reduces tumor xenograft size in vivo. In a series of carcinoma cell lines, the IC50 for proliferation ranged from 120 nmol/L (Colo205) to >8.5 μmol/L (OV202). The addition of stimulatory ligands was unnecessary for the antiproliferative effect in MCF-7 and OV202 cells. BMS-554417 treatment inhibited IGF-IR and insulin receptor signaling through extracellular signal-related kinase as well as the phosphoinositide 3-kinase/Akt pathway, as evidenced by decreased Akt phosphorylation at Ser473. At doses that inhibited proliferation, the compound also caused a G0-G1 arrest and prevented nuclear accumulation of cyclin D1 in response to LR3 IGF-I. In Jurkat T-cell leukemia cells, this agent triggered apoptotic cell death via the mitochondrial pathway. BMS-554417 was orally bioavailable and significantly inhibited the growth of IGF1R-Sal tumor xenografts in vivo. BMS-554417 is a member of a novel class of IGF-IR/insulin receptor inhibitors that have potential clinical applications because of their antiproliferative and proapoptotic activity in vitro and in vivo. (Cancer Res 2006; 66(1): 362-71)

Abstract Polychlorinated biphenyls (PCB) have been suspected as possible contributors to increasing non-Hodgkin's lymphoma incidence during the latter half of the 20th century based on their toxicologic properties and provocative epidemiologic reports. We investigated PCBs and other organochlorines and risk of non-Hodgkin's lymphoma in a population-based case-control study in the United States. Congeners of PCBs (including coplanar congeners), dioxins, furans and pesticides or pesticide metabolites were measured in plasma of 100 untreated cases and 100 control subjects. We used a multiple imputation procedure to fill in missing values of levels determined to be below the detection limits. Risks of non-Hodgkin's lymphoma associated with each analyte were estimated using conditional logistic regression for the continuous measure, exposure quartiles, trend across quartile categories, and exposures above the 95th percentile. Certain PCB congeners were associated with increased risk of non-Hodgkin's lymphoma, including coplanar PCBs 156, 180, and 194, with odds ratios for the highest versus lowest quartile ranging from 2.7 to 3.5, and significant trends. Each of the furan congeners was associated with risk of non-Hodgkin's lymphoma, as were total furans, with 3.5-fold increased risk for the highest versus lowest quartile and a significant trend across quartiles (P = 0.006). The toxic equivalency quotient (TEQ), a summed metric that weights congeners by their dioxin-like potency, was associated with non-Hodgkin's lymphoma, with 35% increased risk per 10 TEQ pg/g lipid (95% confidence interval, 1.02-1.79). Our results add to existing literature, which suggests that exposure to organochlorines contributes to non-Hodgkin's lymphoma risk; these risks were most apparent for certain PCBs and furans.

Abstract Deletion of phenylalanine 508 (ΔF508) accounts for nearly 70% of all mutations that occur in the cystic fibrosis transmembrane conductance regulator (CFTR). The ΔF508 mutation is a class II processing mutation that results in very little or no mature CFTR protein reaching the apical membrane and thus no cAMP-mediated Cl− conductance. Therapeutic strategies have been developed to enhance processing of the defective ΔF508 CFTR molecule so that a functional cAMP-regulated Cl− channel targets to the apical membrane. Sarcoplasmic/endoplasmic reticulum calcium (SERCA) inhibitors, curcumin and thapsigargin, have been reported to effectively correct the CF ion transport defects observed in the ΔF508 CF mice. We investigated the effect of these compounds in human airway epithelial cells to determine if they could induce ΔF508 CFTR maturation, and Cl− secretion. We also used Baby Hamster Kidney cells, heterologously expressing ΔF508 CFTR, to determine if SERCA inhibitors could interfere with the interaction between calnexin and CFTR and thereby correct the ΔF508 CFTR misfolding defect. Finally, at the whole animal level, we tested the ability of curcumin and thapsigargin to (1) induce Cl− secretion and reduce hyperabsorption of Na+ in the nasal epithelia of the ΔF508 mouse in vivo, and (2) induce Cl− secretion in intestine (jejunum and distal colon) and the gallbladder of the ΔF508 CF mouse. We conclude that curcumin and thapsigargin failed to induce maturation of ΔF508 CFTR, or induce Cl− secretion, as measured by biochemical and electrophysiologic techniques in a variety of model systems ranging from cultured cells to in vivo studies.

A number of recently developed and promising approaches to antitumoral immunotherapy are being investigated as potential treatments for advanced prostate cancer. These approaches largely revolve around strategies to increase antigen-specific T-cell activation against prostate tumors as well as precise manipulations of critical co-regulatory receptors that help to maintain and prolong the activity of antigen-presenting cells and T cells that are capable of mediating tumor regression. Herein, we describe the experience with the most recent and promising approaches pertaining to prostate cancer immunotherapy. Additionally, we discuss the mechanistic basis for these approaches as well as current limitations that must still be addressed in order to propel immunotherapy into the forefront of prostate cancer treatment.