Genasense (Bcl-2 antisense)奥利默森钠--反义药物靶向抗癌药

Full Name: Genasense?(oblimersen sodium)

Other Names: Bcl-2 antisense oligonucleotide, G-3139

Description: Antisense drug (intravenous)

Phase: III

Company: Genta Incorporated

www.genta.com

What It Is

Genasense is an antisense drug being investigated for use as a treatment

for myeloma and other cancers, such as melanoma, leukemia, lymphoma, an

d cancers of the lung, prostate, and colon. The agent is being used to i

ncrease the cancer-killing activity of standard anticancer therapy

How It Works

Overview

In myeloma cells and other tumor cells, resistance to anticancer therapy

is associated with the presence of a protein called Bcl-2. Genasense is a

drug that turns off the production of the Bcl-2 protein, which may incre

ase a tumor cell’s sensitivity to therapy and ultimately, cause

cell death.

Details About Antisense Drugs

Genasense is a novel type of drug known as an antisense drug. What is di

fferent about antisense drugs is that they are designed to block the pro

duction of specific proteins. This allows for targeted therapy to the ca

ncer cell with potentially minimal side effects to normal cells.

Proteins are important in most of a cell’s functions and in their survi

val and growth. Genes, which are composed of DNA, provide the "blueprin

t" for the cell to make proteins. In order for a DNA code to be transla

ted into a protein, an intermediate step is required whereby the DNA is

transcribed into a message that the cell can understand. This message is

known as messenger RNA, or mRNA for short. The mRNA then allows the pro

tein to be made.

Antisense drugs are small, chemically modified strands of DNA that are c

omplementary to the specific mRNA (hence the term "anti") that codes f

or the protein (the "sense"). Antisense drugs are designed to bind to

these mRNAs. Once bound to the mRNA, subsequent protein production is st

opped.

Details About Genasense’s Mechanism of Action

Genasense blocks the production of Bcl-2, a protein made by cancer cells

that is thought to block chemotherapy-induced cell death. By reducing t

he amount of Bcl-2 in cancer cells, Genasense may enhance the effectiven

ess of current anticancer therapy.

The figures below show how Bcl-2 prevents chemotherapy-induced cell deat

h and how Bcl-2 blocks this pathway, thus allowing cell death.

In animal studies, when Genasense is used in combination with other anti

cancer treatments, including chemotherapy, radiation, and immunotherapy,

there appears to be a synergistic (additive) killing effect. As a singl

e-agent, Genasense also appears to have some direct killing effects on m

yeloma cells and may inhibit angiogenesis (the growth of new blood vesse

ls).

How It Is Administered

Genasense is given as a continuous intravenous infusion using a portable

pump, typically over the period of 5 to 7 days, followed by 1 to 3 week

s off. In clinical trials, a 3-week cycle is commonly used and may be re

peated for many months, depending on the trial.

Potential Side Effects

Since 1995, more than 1,000 patients have been treated with Genasense. T

he most common side effects observed in clinical trials have been low-gr

ade fever and fatigue. Thrombocytopenia (low platelet counts) has been o

bserved in some patients who are also receiving myelosuppressive (bone m

arrow-suppressing) drugs.

Genasense increases the incidence of side effects, particularly fever. I

t also increases laboratory abnormalities, particularly low neutrophil c

ounts (neutropenia) and thrombocytopenia. Most of the increases are mild

to moderate in severity and return to baseline or near baseline. The ty

pes of side effects seen were similar to those seen with chemotherapy (e

g, low blood counts, nausea, or vomiting). No new or unique side effects

were noted. Catheter-related complications, such as infection, may also

occur. Despite an increased incidence of serious treatment-emergent adv

erse events observed with the combination of Genasense and chemotherapy,

the percentage of patients who died or were discontinued due to adverse

events was comparable to that observed with chemotherapy alone.

Preclinical Studies

In the laboratory, Genasense has been shown to&n