Chemosensitisation of malignant melanoma by BCL2 antisense therapy

Citation
B. Jansen et al., Chemosensitisation of malignant melanoma by BCL2 antisense therapy, LANCET, 356(9243), 2000, pp. 1728-1733
Citations number
26
Language
INGLESE
art.tipo
Article
Categorie Soggetti
General & Internal Medicine","Medical Research General Topics
Journal title
LANCET
ISSN journal
0140-6736 → ACNP
Volume
356
Issue
9243
Year of publication
2000
Pages
1728 - 1733
Database
ISI
SICI code
0140-6736(20001118)356:9243<1728:COMMBB>2.0.ZU;2-O
Abstract
Background Chemoresistance of malignant melanoma has been linked to express ion of the proto-oncogene BCL2. Antisense oligonucleotides (ASO) targeted a gainst BCL2 mRNA decreased BCL2 protein concentrations, increased tumour-ce ll apoptosis, and led to tumour responses in a mouse xenotransplantation mo del when combined with systemic dacarbazine. This phase I-II clinical study investigated the combination of BCL2 ASO (augmerosen, Genasense, G3139) an d dacarbazine in patients with advanced malignant melanoma expressing BCL2. Methods In a within-patient dose-escalation protocol, 14 patients with adva nced malignant melanoma were given augmerosen intravenously or subcutaneous ly in daily doses of 0.6-6.5 mg/kg plus standard dacarbazine treatment (tot al doses up to 1000 mg/m(2) per cycle). Toxicity was scored by common toxic ity criteria. Plasma augmerosen concentrations were assayed by high-perform ance liquid chromatography. In serial tumour biopsy samples, BCL2 protein c oncentrations were measured by western blotting and tumour-cell apoptosis w as assessed. Findings The combination regimen was well tolerated, with no dose-limiting toxicity. Haematological abnormalities were mild to moderate. Lymphopenia w as common, but no febrile neutropenia occurred. Higher doses of augmerosen were associated with transient fever. Four patients had liver-function abno rmalities that resolved within 1 week. Steady-state plasma concentrations o f augmerosen were attained within 24 h, and increased with administered dos e. By day 5, daily doses of 1.7 mg/kg and higher led to a median 40% decrea se in BCL2 protein in melanoma samples compared with baseline, concomitantl y with increased tumour-cell apoptosis, which was greatly increased after d acarbazine treatment. Six patients have shown antitumour responses (one com plete, two partial, three minor). The estimated median survival of ail pati ents now exceeds 12 months. Interpretation Systemic administration of augmerosen downregulated the targ et BCL2 protein in metastatic cancer. Such downregulation of BCL2, combined with standard anticancer therapy, offers a new approach to the treatment o f patients with resistant neoplasms.