Checkpoint Kinase and Wee1 Inhibitors as Anticancer Therapeutics - DNA Repair in Cancer Therapy - page 208

TABLE 10.1 DNA Damaging Agents

Drugs Mechanism of action Tumor type

ALKYLATING AGENTS

Cyclophosphamide DNA cross-linker Breast, ovarian, small-cell lung, non-

Hodgkin's lymphoma, lymphoma,
leukemias, neuroblastoma

Cisplatin, carboplatin, oxaliplatin DNA cross-linker, adduct formation Testicular, ovarian, head and neck,

lymphoma, colorectal, gastric, pancreatic

ANTI-METABOLITES

5-Fluorouracil, capecitabine (prodrug
of 5-FU)

Inhibition of thymidylate synthesis Colorectal, bladder, gastric, pancreatic,

head and neck, breast

Gemcitabine Inhibition of DNA synthesis and inhibition

of DNA polymerase

Pancreatic, NSCLC

Fludarabine Inhibition of DNA synthesis, DNA polymerase

and ribonucleotide reductase

Chronic lymphocytic leukemia

Pemetrexed Inhibition of thymidylate synthesis Advanced or metastatic NSCLC of non-

squamous hostology

TOPOISOMERASE INHIBITORS

Doxorubicin, daunorubicin DNA intercalator, inhibition of DNA

topoisomerases I and II

Breast, ovarian, gastric, lymphomas,
AML, ALL

Irinotecan, topotecan Inhibition of DNA topoisomerase I Colorectal, NSCLC, SCC, ovarian,

pancreatic, gastric

Etoposide Inhibition of topoisomerase II NSCLC, SCLC, testicular, leukemias

Radiation DNA-strand breakage

results in cell cycle arrest allowing time for DNA repair
processes to complete. 17,18 Checkpoint kinases 1 (Chk1)
and 2 (Chk2) are serine/threonine kinases that are
downstream of ATM and ATR and play a critical role
in determining cellular responses to DNA damage,
primarily in the regulation of cell cycle arrest. 19,20
Following activation, Chk1 phosphorylates a number
of serine residues on the protein phosphatase Cdc25a,
facilitating recognition by ubiquitin ligases. Ubiquitina-
tion leads to proteolysis and thus the cells ability to drive
progression through the S phase is halted. 21 e 24 Chk1
also phosphorylates Cdc25c, preventing dephosphory-
lation and activation of CDK1, which in turn results in
cell cycle arrest in the G2 phase. 25 e 27
Further support for the pivotal role of Chk1 in cell
cycle checkpoint control has come from siRNA studies
where it has been demonstrated that Chk1 is an impor-
tant regulator of the S, intra-S, and the G 2 -M phase
checkpoints. 21,28 e 30
Activation of Chk2 is initiated by factors that induce
SSBs, such as replication stress or chemotherapeutic
agents. Once activated, the effects of Chk2 on the effector
proteins Cdc25a, Cdc25c, and p53 are similar to those
mediated by Chk1. 22,31 e 33

Although their effects on downstream pathways
share some similarities, inhibition of Chk1 or Chk2
may have profoundly different outcomes. For example,
knockout animal studies revealed drastic differences in
phenotype between Chk1 and Chk2 null mice. Chk1
( / ) mice are embryonic lethal , whereas Chk2

( ) mice are viable and appear normal. However,

tissues from Chk2 / mice do show significant defects
in G 1 /S checkpoint and IR-induced apoptosis. 34
Recently, further insight was gained into the inter-
relationship of Chk1 and Chk2 by the generation of
conditional mutant mice in which Chk1 was only
deleted in the T-lineage. 35 It was found that in the
absence of Chk1, the transition of CD4 CD8 double-
negative thymocytes to CD4 þ CD8 þ double-positive cells
was blocked by an increase in apoptosis. The loss of
Chk1 resulted in the activation of Chk2 in these thymo-
cytes and conversely the loss of Chk2 resulted in the acti-
vation of Chk1. These data suggest that with Chk1
deletion, cross-talk between the pathways leads to
Chk2-induced apoptosis. Therefore, a dual inhibitor of
both Chk1 and Chk2 might provide some protective
effects on normal tissues such as thymocytes. Chk2 has
also been shown to be modified in Chk1lox/ ES cells

/