BCL-2 ANTISENSE THERAPY IN PATIENTS WITH NON-HODGKIN-LYMPHOMA

Background Overexpression of BCL-2 is common in non-Hodgkin lymphoma a nd leads to resistance to programmed cell death (apoptosis) and promot es tumorigenesis. Antisense oligonucleotides targeted at the open read ing frame of the BCL-2 mRNA cause a specific down-regulation of BCL-2 expression which leads to increased apoptosis. Lymphoma grown in labor atory animals responds to BCL-2 antisense oligonucleotides with few to xic effects. We report the first study of BCL-2 antisense therapy in h uman beings. Methods A daily subcutaneous infusion of 18-base, fully p hosporothioated antisense oligonucleotide was administered for 2 weeks to nine patients who had BCL-2-positive relapsed non-Hodgkin lymphoma . Toxicity was scored by the common toxicity criteria, and tumour resp onse was assessed by computed tomography scan. Efficacy was also asses sed by quantification of BCL-2 expression; BCL-2 protein levels were m easured by flow cytometry in samples from patients. Findings During th e course of the study, the daily dose of BCL-2 antisense was increased incrementally from 4.6 mg/m(2) to 73.6 mg/m(2) No treatment-related t oxic effects occurred, apart from local inflammation at the infusion s ite. In two patients, computed tomography scans showed a reduction in tumour size (one minor, one complete response). In two patients, the n umber of circulating lymphoma cells decreased during treatment. In fou r patients, serum concentrations of lactate dehydrogenase fell, and in two of these patients symptoms improved. We were able to measure BCL- 2 levels by flow cytometry in the samples of five patients, two of who m had reduced levels of BCL-2 protein. Interpretation In patients with relapsing non-Hodgkin lymphoma, BCL-2 antisense therapy led to an imp rovement in symptoms, objective biochemical and radiological evidence of tumour response, and down-regulation of the BCL-2 protein in some p atients. Our findings are encouraging and warrant further investigatio ns of BCL-2 antisense therapy in cancer treatment.