MK-1775, a small molecule Wee1 inhibitor, enhances anti-tumor efficacy of various DNA-damaging agents, including 5-fluorouracil.
MK-1775 is a potent and selective small molecule Wee1 inhibitor. Previously we have shown that it abrogated DNA damaged checkpoints induced by gemcitabine, carboplatin, and cisplatin and enhanced the anti-tumor efficacy of these agents selectively in p53-deficient tumor cells. MK-1775 is currently in Phase I clinical trial in combination with these anti-cancer drugs. In this study, the effects of MK-1775 on 5-fluorouracil (5-FU) and other DNA-damaging agents with different modes of action were determined. MK-1775 enhanced the cytotoxic effects of 5-FU in p53-deficient human colon cancer cells. MK-1775 inhibited CDC2 Y15 phosphorylation in cells, abrogated DNA damaged checkpoints induced by 5-FU treatment, and caused premature entry of mitosis determined by induction of Histone H3 phosphorylation. Enhancement by MK-1775 was specific for p53-deficient cells since this compound did not sensitize p53-wild type human colon cancer cells to 5-FU in vitro. In vivo, MK-1775 potentiated the anti-tumor efficacy of 5-FU or its prodrug, capecitabine, at tolerable doses. These enhancements were well correlated with inhibition of CDC2 phosphorylation and induction of Histone H3 phosphorylation in tumors. In addition, MK-1775 also potentiated the cytotoxic effects of pemetrexed, doxorubicin, camptothecin, and mitomycin C in vitro. These studies support the rationale for testing the combination of MK-1775 with various DNA-damaging agents in cancer patients.
Hirai
Hiroshi
H
Department of Oncology, Banyu Tsukuba Research Institute, Merck Research Laboratories, 3 Okubo, Tsukuba, Ibaraki, Japan. yrdyc661@yahoo.co.jp
Arai
Tsuyoshi
T
Okada
Megumu
M
Nishibata
Toshihide
T
Kobayashi
Makiko
M
Sakai
Naoko
N
Imagaki
Kazuhide
K
Ohtani
Junko
J
Sakai
Takumi
T
Yoshizumi
Takashi
T
Mizuarai
Shinji
S
Iwasawa
Yoshikazu
Y
Kotani
Hidehito
H
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002166:Camptothecin / Q000494:pharmacology; D000069287:Capecitabine; D020169:Caspases / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D004249:DNA Damage / Q000187:drug effects*; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D005434:Flow Cytometry; D005472:Fluorouracil / Q000031:analogs & derivatives / Q000494:pharmacology*; D005971:Glutamates / Q000494:pharmacology; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology; D006657:Histones / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D016685:Mitomycin / Q000494:pharmacology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000068437:Pemetrexed; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011744:Pyrimidinones; D051381:Rats; D011916:Rats, Inbred F344; D011923:Rats, Nude; D023041:Xenograft Model Antitumor Assays
D000903:Antibiotics, Antineoplastic; D000964:Antimetabolites, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D018797:Cell Cycle Proteins; D005971:Glutamates; D006657:Histones; D009687:Nuclear Proteins; D011720:Pyrazoles; D011743:Pyrimidines; D011744:Pyrimidinones; D000068437:Pemetrexed; D003841:Deoxycytidine; D016685:Mitomycin; D006147:Guanine; D000069287:Capecitabine; D004317:Doxorubicin; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; D020169:Caspases; C549567:adavosertib; D005472:Fluorouracil; D002166:Camptothecin