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Growth Factor Receptor Blockade Moving From Laboratory to Clinic

Growth Factor Receptor Blockade Moving From Laboratory to Clinic

PARIS, France--Overexpression of growth factor receptors correlates
with a poor prognosis in many malignancies, including breast,
bladder, and lung cancer, and new evidence suggests that growth
factor receptors may be an important target for anticancer therapy,
John Mendelsohn, MD, said at the Fifth International Congress
on Anti-Cancer Chemotherapy.

The rationale for this novel therapeutic approach, said Dr. Mendelsohn,
of Memorial Sloan-Kettering Cancer Center, also stems from the
observations that most cells require growth factors to proliferate,
and that about one third of proto-oncogenes code for growth factors,
their receptors, or biochemical steps in the signal transduction
pathways activated by the receptors.

Moreover, he noted, transfection of growth factors into nonmalignant
cells can cause these cells to behave in a malignant fashion.
Thus, if the actions of growth factors on their receptors can
be interrupted therapeutically, it may be possible to block cellular
proliferation.

Growth factors may induce cellular proliferation, either through
autocrine stimulation or through stimulation of adjacent cells,
Dr. Mendelsohn told the conference audience. For example, he said,
platelet-derived growth factor (PDGF) produced by breast cancer
cells stimulates fibroblast PDGF receptors, causing the fibroblasts
to produce IGF (insulin-like growth factor), which then in turn
goes back and autostimulates the breast cancer cells.

To illustrate autostimulation of cells, he described how the portion
of the epidermal growth factor (EGF) receptor that exists outside
the cell membrane can be stimulated by EGF or by transforming
growth factor-alpha (TGF-alpha), both of which are often produced
by the same cell. The stimulated receptor then activates its intrinsic
tyrosine kinase, leading to protein phosphorylation and, eventually,
to cellular proliferation.

Dr. Mendelsohn and his colleagues have produced monoclonal antibodies
that block the binding of EGF to its receptor, and thereby inhibit
EGF- and TGF-alpha-induced activation of tyrosine kinase. "This
is not immunotherapy--this is a drug that will block the enzyme
tyrosine kinase," he stressed, pointing out that even antibody
fragments that lack immune activity can still inhibit cellular
growth.

Although very early administration of these monoclonal antibodies
can completely inhibit human tumor growth in nude mice, well-established
tumors are more resistant to cure. However, Dr. Mendelsohn said,
in combination with such cytotoxic agents as platinum, doxorubicin,
or paclitaxel (Taxol), EGF receptor blockade can eliminate established
tumors in xenograft models.

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