Biology Reference
In-Depth Information
TABLE 7.2 Role of HRR in the Response to DNA Damaging Anticancer Agents
Anticancer agents
Example of cancer type
DNA damage
Established/likely role of HRR
ALKYLATING AGENTS
MONOFUNCTIONAL ALKYLATORS
O
6
-methylguanine
Temozolomide
Glioblastoma
Tolerance pathway downstream of
MMR
BIFUNCTIONAL ALKYLATORS
Mitomycin C (MMC)
Anal cancer, germ cell
tumors, lung cancer
Interstrand crosslinks
Fork repair and restart, particularly
dependent on FA pathway
Cyclophosphamide (nitrogen
mustard)
Breast cancer, lymphoma,
leukemia
Interstrand crosslinks
Expected to be similar to mitomycin C
Chlorambucil (nitrogen
mustard)
CLL, Hodgkin's lymphoma
Interstrand crosslinks
Expected to be similar to mitomycin C
Melphalan (nitrogen mustard)
Multiple myeloma
Interstrand crosslinks
Expected to be similar to mitomycin C
BCNU (nitrosurea)
Glioma
Interstrand crosslinks
Expected to be similar to mitomycin C
ANTHRACYCLINES
Adriamycin
Breast cancer
Topoisomerase II
-associated DSB
DSB repair in late S/G2 repair
fork repair and restart
Bleomycin
Hodgkin's lymphoma,
testicular cancer
Radiomimetic DSB
DSB repair in late S/G2
ANTIMETABOLITES
5-fluorouracil (5FU)
Gastrointestinal cancers
Inhibits thymidylate
synthetase (TS)
Unclear, HRR defect may be protective
Gemcitabine
Pancreatic cancer
Inhibits TS
Interferes with HRR machinery
Hydroxyurea
Cervical cancer, leukemia
Depletes dntp pools
Fork repair and restart
Pemetrexed
Lung cancer, mesothelioma
Inhibits several enzymes
including TS
Unknown
Thiopurines
Trials in breast cancer
6-thioguanine
Likely similar to temozolomide
PLATINUM DRUGS
Cisplatin, carboplatin
Lung cancer, ovarian cancer,
head and neck cancer,
testicular cancer
Intrastrand crosslinks,
interstrand crosslinks
(
Fork repair and restart
<
10%)
Oxaliplatin
Colorectal cancer
Less interstrand crosslinks
than cisplatin
TOPOISOMERASE INHIBITORS
TOPOISOMERASE I
Irinotecan, camptothecan
Lung cancer
SSB at forks
Fork repair and restart
TOPOISOMERASE II
Etoposide
Lung cancer
Topoisomerase II-associated
DSB
DSB repair in late S/G2 repair fork
repair and restart
induced by methylating agents such as temozolomide,
which isused in the treatment of glioblastomamultiforme.
O
6
-methylguanine-mediated cell death requires an active
MMR pathway during replication and is either dependent
on the formation of DSB due to futile MMR cycles, or
alternatively direct apoptotic signaling by the MMR
complex. HRR deficient cells are hypersensitive to
O
6
-methylguanine, consistent with an inability to tolerate
