Antisense oligonucleotides in the treatment of non-small-cell lung cancer.

Abstract:

:Antisense oligonucleotides (ASONs) are one of the new classes of molecularly targeted agents that have transitioned from the laboratory into clinical trials. Rational drug design has resulted in agents directed against a number of important cellular targets, including the mRNA of bcl-2, protein kinase (PK) C-alpha, PKA-I, H-ras, c-raf, R1 and R2 subunit of ribonucleotide reductase, and transforming growth factor beta2. These drugs are well tolerated with favorable toxicity profiles, and preliminary studies have demonstrated that they can be feasibly combined with chemotherapy. Plasma half-life is short, generally necessitating continuous prolonged intravenous infusion. Shorter administration schedules are being investigated. Efficacy has been demonstrated in early-phase studies in non-small-cell lung cancer (NSCLC), non-Hodgkin's lymphoma, ovarian cancer, melanoma, and prostate cancer. Molecular correlative studies with peripheral blood mononuclear cells and tumor tissue have demonstrated suppression of target proteins, suggesting that these drugs are indeed reaching the target. Here we discuss the current status of development of ASONs, focusing on LY900003 (formerly ISIS 3521), an agent directed against PKC-alpha currently under study in NSCLC. Phase III studies will determine the ultimate role these agents will play in the treatment of cancer. Future areas of study include combination with radiation and other molecularly targeted agents, alternative dosing schedules, liposomal administration, and the development of new antisense agents directed against additional molecular targets.

journal_name

Clin Lung Cancer

journal_title

Clinical lung cancer

authors

Davies AM,Gandara DR,Lara PN Jr,Mack PC,Lau DH,Gumerlock PH

doi

10.3816/clc.2003.s.007

keywords:

subject

Has Abstract

pub_date

2003-01-01 00:00:00

pages

S68-73

eissn

1525-7304

issn

1938-0690

pii

S1525-7304(11)70313-8

journal_volume

4 Suppl 2

pub_type

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