Epigenetic changes involved in
cancer development, unlike genetic changes, are reversible.
DNA methyltransferase and
histone deacetylase inhibitors show antiproliferative effects in vitro, through
tumor suppressor reactivation and induction of apoptosis. Such inhibitors have shown activity in the treatment of hematologic disorders but there is little data concerning their effectiveness in treatment of solid
tumors. FHIT, WWOX and other tumor suppressor genes are frequently epigenetically inactivated in
lung cancers.
Lung cancer cell clones carrying conditional FHIT or WWOX transgenes showed significant suppression of xenograft
tumor growth after induction of expression of the FHIT or WWOX transgene, suggesting that treatments to restore endogenous Fhit and Wwox expression in
lung cancers would result in decreased tumorigenicity. H1299
lung cancer cells, lacking Fhit, Wwox,
p16(INK4a) and Rassf1a expression due to epigenetic modifications, were used to assess efficacy of epigenetically targeted protocols in suppressing growth of lung
tumors, by injection of 5-aza-2-deoxycytidine (AZA) and
trichostatin A (
TSA) in nude mice with established H1299
tumors. High doses of intraperitoneal AZA/
TSA suppressed growth of small
tumors but did not affect large
tumors (200 mm(3)); lower AZA doses, administered intraperitoneally or intratumorally, suppressed growth of small
tumors without apparent toxicity. Responding
tumors showed restoration of Fhit, Wwox, p16(
INKa), Rassf1a expression, low mitotic activity, high apoptotic fraction and activation of
caspase 3. These preclinical studies show the therapeutic potential of restoration of
tumor suppressor expression through epigenetic modulation and the promise of re-expressed
tumor suppressors as markers and effectors of the responses.