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.