Trastuzumab has opposing effects on SN-38-induced double-strand breaks and cytotoxicity in HER2-positive gastric cancer cells depending on administration sequence.
OBJECTIVE
We investigated the effects of trastuzumab, an anti-HER2 humanized monoclonal antibody, on DNA breaks induced by SN-38, a topoisomerase-1 inhibitor, in gastric cancer cell lines positive or negative for HER2 expression.


METHODS
NCI-N87 (HER2+) and MKN74 (HER2-) cells were exposed to SN-38 in the presence or absence of trastuzumab. Trastuzumab was added either prior to or after SN-38. Effects of trastuzumab on the induction of gamma-H2AX, a marker of DNA double-strand breaks, the cytotoxicity of SN-38 and cell cycle progression were determined.


RESULTS
When trastuzumab was administered following SN-38, it increased γH2AX levels and cytotoxicity of SN-38 in NCI-N87 cells, but not in MKN74 cells. In contrast, pretreatment with trastuzumab reduced SN-38-induced γH2AX expression and cytotoxicity of SN-38 in NCI-N87 cells, but not in MKN74 cells. Trastuzumab delayed cell cycle progression in NCI-N87 cells only.


CONCLUSIONS
Trastuzumab has opposing effects on SN-38-induced double-strand breaks and cytotoxicity depending on the order of administration of the two agents.
First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Mihoko
M
Yamade
Mitsushige
M
Sugimoto
Masafumi
M
Nishino
Takahiro
T
Uotani
Shu
S
Sahara
Moriya
M
Iwaizumi
Takanori
T
Yamada
Satoshi
S
Osawa
Ken
K
Sugimoto
Hiroaki
H
Miyajima
Takahisa
T
Furuta
D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects*; D004334:Drug Administration Schedule; D005434:Flow Cytometry; D006801:Humans; D000077146:Irinotecan; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D000068878:Trastuzumab; D014407:Tumor Cells, Cultured
D061067:Antibodies, Monoclonal, Humanized; D002166:Camptothecin; D000077146:Irinotecan; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab