Abstract
Selenium, a known antioxidant used in chemoprevention, has recently been shown to improve the efficacy of chemotherapy agents and mediate anti-angiogenic effects in preclinical solid tumor models. Prior data has also shown that sodium selenite can induce apoptosis of human acute myeloid leukemia (AML) cells in vitro. While the use of high non-toxic doses of selenium has been demonstrated to effectively enhance the therapeutic efficacy and selectivity of various anti-cancer drugs in multiple solid tumor xenograft models (Cao et al, Clin Canc Res10: 2561–2569, 2004), the in vivo effects of selenium compounds in hematological malignancies have not been extensively explored. Our laboratory has previously demonstrated the preclinical efficacy of VEGF inhibitors in human leukemia xenograft models. Here we investigated the in vitro and in vivo effects of seleno-L-methionine (SLM), alone and in combination with chemotherapy and anti-VEGF antibody, in human AML. The mechanism of action, dosage, and time course of SLM effects on AML cells (ML-2 and HL60) in vitro were determined using colorimetric (CCK-8) viability, tritiated thymidine proliferation, and Annexin-V flow cytometric assays. SLM therapy resulted in dose dependent inhibition of AML proliferation with marked induction of apoptosis and a 67–92% reduction in viable cells at 400–500 μM. Ten million AML cells (ML-2 and HL60-luciferase) were then subcutaneously engrafted into immunodeficient (SCID/SCID) mice. ML-2 tumor bearing mice were treated with PBS (vehicle), SLM (200 mcg p.o. daily), cytarabine (Ara-C 2 mg i.p. for 3 days), or combination SLM + Ara-C therapy for over two weeks. SLM showed no effective modulation of therapeutic efficacy and toxicity in AML tumor models, when combined with Ara-C. Neither SLM nor Ara-C alone or in combination resulted in significant reduction of AML growth. ML-2 and HL60-luciferase tumor bearing mice were then treated with PBS, SLM (200 mcg p.o. daily), anti-VEGF antibody bevacuzimab (BV 100mcg i.p. twice weekly), or SLM + BV for three weeks. Disease progression was monitored by tumor volume, end tumor weight, and bioluminescent imaging. Although SLM alone was ineffective in reducing HL60 leukemia growth, SLM + BV combination therapy effectively induced a 75% reduction in mean tumor volume after 21 days of treatment which was statistically greater than BV therapy alone (62% reduction). Synergistic effects of SLM+BV therapy was also confirmed by differences in mean tumor weights and bioluminescent imaging as compared with single agent BV and SLM treated mice. Similar results were seen in the ML-2 AML xenograft model.
Conclusions: SLM improved the anti-angiogenic and anti-tumor effects of anti-VEGF therapy with bevacizumab in human AML xenograft models. Additional studies investigating the mechanisms of action of these synergistic effects will be presented.
Efficacy and Concentration-Response of Murine Anti-VEGF Monoclonal Antibody in Tumor-Bearing Mice and Extrapolation to Humans