Abstract

Introduction

Mantle cell lymphoma (MCL), an incurable B cell lymphoma, consistently over expresses bcl-2 despite not carrying the t(14;18). The attenuation of apoptosis by bcl-2 is thought to contribute to the malignant process and increase resistance to some cytotoxic agents. We recently demonstrated that GX15-070, a small molecular inhibitor of the BH3 binding groove of bcl-2, has activity against MCL cell lines in vitro. We set out to assess the effect of GX15-070 alone and in combination with Vincristine on the viability of MCL cells in vitro and in vivo.

Methods

3 previously characterized bcl-2 over expressing MCL cell lines (JVM-2, Hbl-2, granta) were used. Cells were grown in standard media and exposed to a range of concentrations of GX15-070 with and without Vincristine. Dose-response was assessed by measuring viability at 48 hours using the WST-1 assay. In vivo experiments were conducted on immune deficient mice in which 5×106 cells were injected in the flank then treated IV with GX15-070 (q 2days × 5 doses), Vincristine (q4 days × 3 doses) or both starting 5 days later. Tumours were measured three times weekly.

Results

All three MCL cell lines over-expressed bcl-2 by western blot. Each MCL cell line showed sensitivity to GX15-070 at a range of concentrations. The addition of GX15-070 to low dose Vincristine (10−6) caused significant growth inhibition of each MCL cell line (see table 1).

Discussion

Our results demonstrate that using GX15-070 to target bcl-2 is an effective anti neoplastic approach against MCL cell lines in vitro. In addition, our results suggest that combining Vincristine and GX15-070 is a promising strategy in treating MCL. In vivo experiments to confirm this additive activity are still ongoing and will be presented in full. Initial impressions suggest that there is a rationale for the addition of GX15-070 to current cytotoxic regimens used to treat MCL in the setting of clinical trials.

Table 1:

Effect of Vincristine and GX15-070 on in vitro growth of 3 MCL cell lines

Growth as % age of Control
Cell LineJVM-2HBL-2Granta
Vincristine alone (10-6 mg/ml) 92% 48% 89% 
GX15-070 alone (0.08 uM) 75% 76% 60% 
Vincristine 10-6 mg/ml and GX15-070 0.08 uM 52% 24% 52% 
Growth as % age of Control
Cell LineJVM-2HBL-2Granta
Vincristine alone (10-6 mg/ml) 92% 48% 89% 
GX15-070 alone (0.08 uM) 75% 76% 60% 
Vincristine 10-6 mg/ml and GX15-070 0.08 uM 52% 24% 52% 

Disclosure: No relevant conflicts of interest to declare.

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