Motexafin Gadolinium (MGd) induces apoptosis in lymphoma cell lines by redox mechanisms: Rationale for targeted radiation sensitization with 90Yttrium-zevalin/MGd in relapsed lymphoma

Abstract

3199 Background: MGd is a tumor-selective redox mediator that generates reactive oxygen species such as hydrogen peroxide. MGd enhances the efficacy of ionizing radiation in animal models and is in clinical trials combined with radiation for treatment of solid tumors. We now report the results of MGd activity in various lymphoma cell lines in vitro. These results provide the rationale for an ongoing phase I/II trial combining MGd with 90Yttrium-Zevalin for relapsed non-Hodgkin's lymphoma (NHL). Methods: B-cell lines (HF-1, DHL-4, Ramos), Jurkat and HL60 were cultured in vitro +/- MGd (0–50uM). Cell growth and apoptosis were measured using Annexin-V staining. A modified Fibonacci phase I/II trial is enrolling patients with relapsed NHL to receive combination 90Yttrium-Zevalin with increasing doses of MGd. Patients receive MGd daily days 1 to 4 (with 111Indium-Zevalin) and days 8 to 11 with standard 90Yttrium-Zevalin given day 8. Magnetic resonance imaging (MRI) is used to visualize selective uptake of MGd in tumors. Results: MGd inhibited growth of all cell lines by 60%–80% with an increase in apoptotic cells ranging from 20%–50%. Incubation of HF-1 cells with rituximab alone induced apoptosis in 40% of cells, which increased to over 80% with the addition of MGd. Combination 90Yttrium-Zevalin (0.4 mCi/kg) and MGd (2.5mg/kg) therapy has been well tolerated by the first cohort enrolled/treated. There is one evaluable patient who had a 60% decrease in a 6cm diffuse follicle-center scalp mass ten days following treatment. The mass completely resolved 4 weeks following therapy with associated 80% decrease in bulky follicular lymphoma abdominal disease. A day 4 noncontrast MRI of the scalp mass showed a 30% increase in MRI signal intensity (compared to a pre-MGd scan) indicating selective tumor uptake of MGd. Conclusions: MGd induces apoptosis in various lymphoma cell lines and is additive with rituximab. MGd can be given together with 90Yttrium-Zevalin to achieve targeted radiation sensitization. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pharmacyclics, Inc. Pharmacyclics, Inc. Pharmacyclics, Inc. Pharmacyclics, Inc. Pharmacyclics, Inc. Pharmacyclics, Inc. Pharmacyclics, Inc.