Chemistry Reference
In-Depth Information
enhances resistance to this drug. It has been demonstrated
144
that downregulation
of ERCC1 signifi cantly sensitizes the MMR-defi cient prostate cancer cell line to
cisplatin, where inhibition of the NER pathway had no effect. In addition, a recent
study
21
suggests that homologous recombination status might represent a novel
prognostic marker and possibly also a therapeutic target.
6.5 Implications for Design of Antitumour Platinum Compounds
The occurrence of inherent and acquired resistance to platinum is a major problem
that undermines efforts to effectively treat cancer. This limitation in cancer treat-
ment can be overcome by elucidating the mechanisms underlying resistance to
platinum drugs and then developing ways to treat resistant tumours effectively or
prevent its occurrence.
145
DNA repair is a major resistance mechanism to platinum-
based chemotherapy. Evidence for increased repair of platinum-DNA damage in
resistant cancer cells has been demonstrated by a variety of cellular assays. In human
cells, major intrastrand crosslinks of cisplatin are removed from DNA mainly by the
NER system.
61
Importantly, the repair of major intrastrand crosslinks of cisplatin
may be blocked by high-mobility-group (HMG) domain proteins, and perhaps by other
proteins that bind to damaged DNA,
3,97,146,147
causing drug resistance to be lower.
Thus, the ability of cancer cells to recognize damage induced in DNA by plati-
num antitumour drugs and initiate DNA repair is an important mechanism for
therapeutic resistance and has a negative impact upon therapeutic effi cacy. Pharma-
cological inhibition of DNA repair, therefore, has the potential to enhance effi ciency
of antitumour chemotherapy. It implies that design of new antitumour platinum
drugs should focus on those new platinum complexes that form major adducts with
DNA that are diffi cult to remove by DNA repair systems. This strategy has been
employed by designing and synthesizing antitumour dinuclear platinum complexes
[(
cis
- {Pt - (NH
3
)
2
})
2
( m - OH)( m - pz)]
2+
(pz = pyrazolate)
148
or dinuclear azole-bridged
platinum compounds.
149 - 152
These new platinum complexes exhibit higher toxic
effects in some tumour cell lines and form 1,2-GG instrastrand crosslinks, which
bend DNA markedly less than cisplatin. It has been suggested that these minor
structural changes are not recognized by the DNA repair proteins and in this way
escape repair. This assumption must, however, await further experimental confi rma-
tion. It cannot be excluded that the bulkiness of the adduct in addition to its pro-
pensity to induce only very weak conformational distortions is an important factor
involved in the initiation of DNA repair.
Moreover, the use of inhibitors of DNA repair or DNA damage signalling
pathways also appears to provide an opportunity to enhance or alter the antitumour
effects of platinum agents and to target the genetic differences that exist between
normal and tumour tissue as well.
153
On the other hand, use of DNA repair inhibi-
tors or their combination with such anticancer therapies is also likely to enhance
the risk of mutagenic DNA damage and hence the risk of secondary cancer. Thus,
concepts for antitumour strategies based on DNA repair inhibitors must await
further studies.
