Findings from the United States and United Kingdom describe new data in leukemia research

06-13-2006

Leukemia research advances have been reported from the United States and United Kingdom.

Study 1: PKC-d (protein kinase C-d) was announced as a promising new target in chronic lymphocytic leukemia (CLL) treatment.

"Constitutively activated signaling pathways contribute to the apoptosis-defect of B-CLL cells. Protein kinase C-d is a permanently activated kinase and a putative downstream target of phosphatidylinositol-3 kinase in B-CLL," researchers in the United States reported.

"Blockade of PKC-d by the highly specific inhibitor rottlerin induces apoptosis in chronic lymphocytic leukaemia (CLL) cells," explained I. Ringshausen and colleagues, University of California, San Francisco. "By co-culturing bone marrow stromal and CLL cells, we determined that the proapoptotic effect of rottlerin is not abolished in the presence of survival factors, indicating that a targeted therapy against PKC-d might be a powerful approach for the treatment of CLL patients. The downstream events following rottlerin treatment engage mitochondrial and non-mitochondrial pathways and ultimately activate caspases that execute the apoptotic cell death.

"Herein we report that the inhibition of PKC-d decreases the expression of the important antiapoptotic proteins Mcl-1 and XIAP accompanied by a loss of the mitochondrial membrane potential Delta psi. In addition, we discovered that ZAP-70-expressing cells are significantly more susceptible to rottlerin-induced cell death than ZAP-70 negative cells. We finally observed that rottlerin can augment cell toxicity induced by standard chemotherapeutic drugs."

The researchers concluded, "Conclusively, PKC-d is a promising new target in the combat against CLL."

Ringshausen and colleagues published their study in Leukemia (Mechanisms of apoptosis-induction by rottlerin: therapeutic implications for B-CLL. Leukemia, 2006;20(3):514-520).

For additional information, contact I. Ringshausen, University of California, San Francisco, Center Comprehensive Cancer, Box 0-875, 2340 Sutter St., San Francisco, CA 94115, USA.

Study 2: Cyclophosphamide and fludarabine could be used to treat chronic lymphocytic leukemia (CLL).

"B-cell CLL accounts for 95% of chronic leukemia cases and 25% of all leukemia. Despite the prevalence of CLL, progress in its treatment has been only modest over the past 3 decades," scientists in the United States reported.

"Based upon the ability of fludarabine to produce high-grade remissions especially among patients with low initial tumor mass, and the ability of alkylators to reduce tumor mass, we hypothesized that sequential administration of a limited number of cycles of intermediate-dose cyclophosphamide followed by fludarabine could result in a larger percentage of patients with complete remissions (CRs)," explained M.A. Hussein and colleagues, Southwestern Oncology Group.

"In all, 27 of the 49 eligible patients achieved overall responses of CR, unconfirmed complete remission (UCR), or PR, for a total response rate of 55% (95% confidence interval (CI) 40-69%). Considering the confounding medical issues of this patient population with advanced aggressive disease, the regimen was generally well tolerated."

The researchers concluded, "This study demonstrates that high-dose cyclophosphamide followed by fludarabine was relatively well tolerated in this group of advanced CLL patients. The study's criterion for testing whether the regimen is sufficiently effective to warrant further investigation was met: 14 (32%) of the first 44 eligible patients achieved CR or UCR."

Hussein and colleagues published their study in Leukemia (Cyclophosphamide followed by fludarabine for untreated chronic lymphocytic leukemia: a phase IISWOG TRIAL 9706. Leukemia, 2005;19(11):1880-1886).

For additional information, contact M.A. Hussein, Southwestern Oncology Group, Operat Off, 14980 Omicron Dr., San Antonio, TX 78245, USA.

Study 3: Ingenol 3-angelate has potent antileukemic activity mediated via the delta isoform of protein kinase C.

"Ingenol 3-angelate (PEP005) is a selective small molecule activator of protein kinase C (PKC) extracted from the plant Euphorbia peplus, whose sap has been used as a traditional medicine for the treatment of skin conditions including warts and cancer.

"We report here that PEP005 also has potent antileukemic effects, inducing apoptosis in myeloid leukemia cell lines and primary acute myeloid leukemia (AML) cells at nanomolar concentrations," scientists in United Kingdom said.

"Of importance, PEP005 did not induce apoptosis in normal CD34+ cord blood myeloblasts at up to 2-log concentrations higher than those required to induce cell death in primary AML cells. The effects of PEP005 were PKC dependent, and PEP005 efficacy correlated with expression of PKC-delta," reported P. Hampson and colleagues at the University of Birmingham.

The authors continued, "The delta isoform of PKC plays a key role in apoptosis and is, therefore, a rational potential target for antileukemic therapies.

"Transfection of KG1a leukemia cells, which did not express PKC-delta or respond to PEP005, with enhanced green fluorescent protein (EGFP)-PKC-delta restored sensitivity to induction of apoptosis by PEP005."

Investigators concluded, "Our data, therefore, suggest that activation of PKC-delta provides a novel approach for treatment of acute myeloid leukemia and that screening for PKC-delta expression may identify patients for potential responsiveness to PEP005."

Hampson and colleagues published their study in Blood (PEP005, a selective small-molecule activator of protein kinase C, has potent antileukemic activity mediated via the delta isoform of PKC. Blood, 2005;106(4):1362-8).

For more information, contact P. Hampson, University of Birmingham, MRC Center for Immune Regulation, Division of Immunity and Infection, The Medical School, Birmingham B15 2TT, United Kingdom.

Keywords: Birmingham, United Kingdom, Acute Myeloid Leukemia, Protein Kinase C, Ingenol 3-Angelate/PEP005, Antileukemic Activity, Apoptosis.

This article was prepared by Clinical Oncology Week editors from staff and other reports. Copyright 2006, Clinical Oncology Week via NewsRx.com.