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 category.
Those patients whose tumors have lost the short arm of the first chromosome
(1p) essentially always respond to PCV, and those with combined loss of 1p
and 19q (long arm of chromosome 19) and lack other detectable alterations
have durable responses and long survival times - over 10 years. In contrast,
those whose tumors lack these genetic alterations but harbor others such as
EGFR amplification rarely respond to PCV in a durable manner and have short
survivals - less than 2 years. Hence, genotyping can direct the former group
(1p loss) to initial PCV instead of radiotherapy, the latter group (1p
intact) can bypass the difficulty of PCV therapy, in favor of radiotherapy,
which causes few side effects in patients with short survival times. It is
not known which specific gene(s) loss on 1p and 19q renders susceptibility
to alkylating agents giving rise to this therapeutic advantage.
 Are
there other opportunities to target chemotherapies to specific patient
populations? Yes – the mechanism of resistance to alkylating and methylating
agents has been determined (Esteller et al., 2000). Alkylating (and
methylating) agents cause cell death by binding to DNA, usually the O6
position of guanine. The addition of this alkyl or methyl group to the DNA
backbone results in the formation of lethal cross-links between adjacent
strands of DNA. The cross-linking of double-stranded DNA is inhibited by the
cellular DNA-repair protein O6-methylguanine-DNA methyltransferase (MGMT).
The MGMT protein reverses alkylation at the O6 position of guanine, thereby
averting the formation of cross-links.
MGMT expression is
not uniform in all brain tumors. Approximately 30 percent of gliomas lack
MGMT. This deficiency may increase the sensitivity of brain tumors to
 alkylating
agents. The MGMT gene (chromosome 10q) is not commonly mutated or deleted in
brain tumors. Absence of MGMT expression is caused by epigenetic phenomena -
changes that do not alter the genetic information of the cell. In this case,
methylation of the MGMT promoter leads to gene silencing – an absence of
MGMT gene expression and thus protein expression.
How is MGMT expression status
useful? A recent phase 3 trial demonstrated that among patients with
glioblastoma whose tumor contained a methylated MGMT promoter, a survival
benefit was observed in those treated with temozolomide and radiation;
median survival was 21.7 months as compared to 15.3 months among those who
were assigned to radiation alone (Hegi et al., 2005). In the absence of
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