Cancer Chemotherapy, Theoretical Foundations of
175
c-
bcr
/chr 22
1
2
3
4
5
1
2
3
2
-
1 1
1
2
-
1 1
1
2
-
1 1
c-
abl
/chr 9
p210
p185
bcr
-
abl
fusion
Fig. 1
Chromosomal breakpoints in chronic myelogenous leukemia (CML) and acute
lymphoblastic leukemia (ALL). In CML and ALL, a breakpoint occurs between the frst
exon oF c-
abl
on chromosome 9, translocating most oF c-
abl
to c-
bcr
on chromosome
22. In CML, the translocations in c-
bcr
occur aFter exon 2 or 3, to yield the p210 Fusion
protein, and in Ph-positive ALL, they occur aFter exon 1 to create p185. The solid arrows
indicate CML breakpoints and broken arrows indicate ALL breakpoints.
Both humanized monoclonal antibodies
and small molecules have been developed
against ErbB1 (also known as EGF receptor
and HER1) and ErbB2 (also known as
HER2 and Neu). Herceptin (trastuzumab)
has received regulatory approval as a
single agent for treatment of metastatic
breast cancers expressing ErbB2, whereas
other humanized antibodies against ErbB1
such as Cetuximab remain in clinical
development.
Iressa (ZD1839) is an optimized small
molecule ATP competitive antagonist of
the ErbB1 tyrosine kinase, originally iden-
ti±ed by high-throughput screening and
subsequently shown to be active against
breast cancer cells. Phase II clinical tri-
als with Iressa demonstrated activity in
nonsmall cell lung cancer (NSCLC), squa-
mous cell carcinomas of the head and
neck, and hormone refractory prostate can-
cer. Recently, Iressa was evaluated in a
randomized Phase II study for activity in
advanced NSCLC, where it was found that
it did not provide improvement in survival
when added to standard platinum-based
chemotherapy.
A signi±cant question regarding the clin-
ical utility of mechanism-based drugs like
Iressa relates to how they will be used in
the clinical setting. A relevant administra-
tion schedule and, as mechanism-based
drugs may be cytostatic, identifying an ap-
propriate combination agent and patient
population are likely to be critical determi-
nants in reaching optimal clinical ef±cacy.
previous page 849 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online next page 851 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online Home Toggle text on/off