Safety and Efficacy of a DNA Oligonucleotide Therapy in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma.

Background: PNT2258 is a liposomal formulation that encapsulates multiple copies of PNT100, a native, chemically unmodified, 24-base DNA oligonucleotide designed to target the regulatory region upstream of the B-cell lymphoma 2 (BCL2) gene.

Methods: This phase II, multicenter, single-arm, open-label, 2-stage design study investigated the single-agent activity of PNT2258 in patients with relapsed/refractory DLBCL. Initially, patients had to have a performance status (PS) of ≤2 and prior exposure to CD20-targeted therapy, an alkylating agent, and a steroid with no upper limit.

A Phase 2 Study of PNT2258 for Treatment of Relapsed or Refractory B-Cell Malignancies.

Background: PNT2258 consists of a native, chemically unmodified, 24-base DNA oligonucleotide designed to target the regulatory region upstream of the BCL2 gene, delivered in a protective liposome. Derangement of BCL2-regulated control mechanisms is a defining characteristic of certain malignancies, and it was hypothesized that the oligonucleotide would promote anticancer activity via suppression of BCL2 transcription.

Methods: PNT2258 was evaluated in this, multicenter, nonrandomized, open-label Phase 2 study in 13 participants with relapsed/refractory B-cell malignancies to investigate potential antitumor activity and safety.

Isolation and characterization of a CD34 sub-clone in B-cell lymphoma.

Non-Hodgkin's lymphoma (NHL) is the most common hematological malignancy in the US. Many types remain incurable despite response to initial therapy and achievement of complete remission (CR). Advanced laboratory techniques like multicolor flow cytometry (FCM) and polymerase chain reaction (PCR) have demonstrated persistence of rare malignant cell population post therapy.

Unintended target effect of anti-BCL-2 DNAi.

Introduction: Previous research suggested that a novel compound PNT2258 inhibits B-cell lymphoma 2 () transcription by DNA interference (DNAi) and demonstrated its activity in preclinical xenograft models and in a pilot Phase II clinical trial in non-Hodgkin's lymphoma (NHL). While the drug downregulates at the promoter, mRNA, and protein levels, there is a significant homology (13-16 bases) between PNT100 and a number of promoters of genes involved in cell cycle regulation and survival. In this study, we identify cyclin-dependent kinase-4 () as an unintended target gene of PNT2258 and examine its relevance to NHL.

HDM2 antagonist MI-219 (spiro-oxindole), but not Nutlin-3 (cis-imidazoline), regulates p53 through enhanced HDM2 autoubiquitination and degradation in human malignant B-cell lymphomas.

Background: Lymphomas frequently retain wild-type (wt) p53 function but overexpress HDM2, thereby compromising p53 activity. Therefore, lymphoma is a suitable model for studying the therapeutic value of disrupting the HDM2-p53 interaction by small-molecule inhibitors (SMIs). HDM2 have been developed and are under various stages of preclinical and clinical investigation.

Syncytial giant cell hepatitis associated with chronic lymphocytic leukemia: a case report.

Background: Syncytial giant cell hepatitis (GCH) is an uncommon and an underreported disease entity. In two previously reported cases of GCH in patients with Chronic Lymphocytic Leukemia (CLL) liver failure ensued. Autoimmune and infective causes have been implicated but its etiology remains unclear.

An MDM2 antagonist (MI-319) restores p53 functions and increases the life span of orally treated follicular lymphoma bearing animals.

Background: MI-319 is a synthetic small molecule designed to target the MDM2-P53 interaction. It is closely related to MDM2 antagonists MI-219 and Nutlin-3 in terms of the expected working mechanisms. The purpose of this study was to evaluate anti-lymphoma activity of MI-319 in WSU-FSCCL, a B-cell follicular lymphoma line.

Superior antitumor activity of SAR3419 to rituximab in xenograft models for non-Hodgkin's lymphoma.

Purpose: To investigate the activity of SAR3419, a novel humanized anti-CD19 antibody (huB4), conjugated to a cytotoxic maytansine derivative N(2)'-deacetyl-N(2)'-(4-mercapto-4-methyl-1-oxopentyl) maytansine, in preclinical xenograft models for non-Hodgkin's lymphoma.

Experimental Design: Antitumor activity of SAR3419 was assessed as a single agent and in comparison with conventional therapies using a subcutaneous model for diffuse large B-cell lymphoma (WSU-DLCL2) and a systemic model for follicular small cleaved cell lymphoma (WSU-FSCCL) in mice with severe combined immune deficiency.

Results: Our results showed that in these chemotherapy-resistant models, SAR3419 was more effective than CHOP (cyclophosphamide-Adriamycin-vincristine-prednisone) regimen or rituximab.

SMI of Bcl-2 TW-37 is active across a spectrum of B-cell tumors irrespective of their proliferative and differentiation status.

The Bcl-2 family of proteins is critical to the life and death of malignant B-lymphocytes. Interfering with their activity using small-molecule inhibitors (SMI) is being explored as a new therapeutic strategy for treating B-cell tumors. We evaluated the efficacy of TW-37, a non-peptidic SMI of Bcl-2 against a range spectrum of human B-cell lines, fresh patient samples and animal xenograft models.

Factors affecting bryostatin 1-enhanced 2-CdA cytotoxicity in resistant B-cell chronic lymphocytic leukemia.

Pre-treatment with bryostatin 1 (bryo) has been shown to potentiate the efficacy of (2-chloro-2-deoxyadenosine, cladribine, 2-CdA) in B-cell chronic lymphocytic leukemia (B-CLL) by increasing the ratio of deoxycytidine kinase (dCK) to 5'-nucleotidase (5'-NT) activity. The bryo-induced increase in dCK/5'-NT activity alone has not been a conclusive indication of final clinical outcome. Therefore, we used an ex vivo assay to investigate factors which may affect the bryo-induced enhancement of 2-CdA efficacy in B-CLL patient-derived samples.

Preclinical evaluation of 2-[4-(7-chloro-2-quinoxalinyloxy)phenoxy]-propionic acid as a modulator of etoposide in human Waldenstrom's macroglobulinemia xenograft model.

We have previously reported that XK469 (2-[4-(7-chloro-2-quinoxalinyloxyphenoxy]-propionic acid) enhances topo IIalpha expression in WSU-WM cells in vitro [E. Mensah-Osman et al., Mol.

The Wayne State University Waldenstrom's Macroglobulinemia preclinical model for Waldenstrom's macroglobulinemia.

The Wayne State University Waldenstrom's Macroglobulinemia xenograft model in mice with severe combined immune deficiency (WSU-WM-SCID) is the only preclinical animal model available for this disease. It is based on a permanent, EBV- IgMlambda cell line (WSU-WM) established from a patient with a 10-year history of Waldenstrom's macroglobulinemia (WM). These cells are CD5(-)CD10(+)CD19(+)CD20(+)CD22(+) and have t(8;14) (q24;32), t(12;17) (q24;q21), 2p-.

2-[4-(7-chloro-2-quinoxalinyloxyphenoxy]-propionic acid (XK469), an inhibitor of topoisomerase (Topo) IIbeta, up-regulates Topo IIalpha and enhances Topo IIalpha-mediated cytotoxicity.

Topoisomerase (Topo) IIalpha has proven to be an adequate anticancer target for tumors expressing this enzyme. In this study, we elucidated the effect of 2-[4-(7-chloro-2-quinoxalinyloxyphenoxy]-propionic acid (XK469; a new Topo IIbeta inhibitor) in the modulation of Topo IIalpha levels and sensitivity to Topo IIalpha poisons. We demonstrate by Western blot analysis that indolent B-cell tumors express undetectable levels of this enzyme and are refractory to the effects of Topo IIalpha poisons such as VP16.

2-[4-(7-chloro-2-quinoxalinyloxy)phenoxy]-propionic acid (XK469) inhibition of topoisomerase IIbeta is not sufficient for therapeutic response in human Waldenstrom's macroglobulinemia xenograft model.

The role of DNA topoisomerase (Topo) IIbeta in cancer chemotherapy remains unclear, although this particular isoform has been implicated in drug resistance. In this study, we investigated Topo IIbeta as a target for 2-[4-(7-chloro-2-quinoxalinyloxy)phenoxy]-propionic acid (XK469), a novel synthetic quinoxaline phenoxypropionic acid derivative, in a Waldenstrom's macroglobulinemia (WM) model. In vitro, the WSU-WM cell line was exposed to 1.

Combretastatin-A4 prodrug induces mitotic catastrophe in chronic lymphocytic leukemia cell line independent of caspase activation and poly(ADP-ribose) polymerase cleavage.

We have previously reported that combretastatin-A4 prodrug (CA4P), anantitubulin/antiangiogenic agent isolated from the South African willow tree Combretum caffrum, induced cell death primarily through mitotic catastrophe in a panel of human B-lymphoid tumors. In this study, we investigated the molecular aspects of the mitotic catastrophe and whether or not it shares the same pathways of apoptosis. For this we studied the effect of CA4P on selected markers of apoptosis [caspases 9 and 3, poly(ADP-ribose) polymerase (PARP), bcl-2, and bax] and G2-M protein regulators (p53, MDM2, 14-3-3sigma, GADD45, cdc2, cdc25, chk1, wee1, p21, and cyclin B1).