Enhancement of tumor radioresponse by combined chemotherapy in murine hepatocarcinoma.
OBJECTIVE
Recent studies have shown that local radiotherapy can be an effective component of the treatment for hepatocellular carcinoma. To further improve therapeutic efficacy, use of drugs that can beneficially interact with radiation has been suggested. The purpose of this study was to identify drugs that can enhance radioresponse of murine hepatocarcinoma.


METHODS
C3H/HeJ mice bearing 8 mm tumors of murine hepatocarcinoma, HCa-I, were treated with 25 Gy radiation and one of the following drugs: 5-Fu, 150 mg/kg; adriamycin, 8 mg/kg; cisplatin, 6 mg/kg; paclitaxel, 40 mg/kg; and gemcitabine, 50 mg/kg. Tumor response to the treatment was determined by the use of a tumor growth delay assay and by an enhancement factor. The apoptotic level was assessed in tissue sections. The expression of regulating molecules was analyzed by using western blotting for p53, Bcl-2, Bax, Bcl-XL, Bcl-XS, and p21(WAF1/CIP1).


RESULTS
Among the drugs tested, only gemcitabine enhanced the antitumor effect of radiation, with an enhancement factor of 1.6. The induction of apoptosis by a combination of gemcitabine and radiation was shown as only an additive level. In the analysis of radiation-induced expression of regulating molecules, the most significant change by combining gemcitabine with radiation was the activation of p21(WAF1/CIP1).


CONCLUSIONS
Gemcitabine is the first to show an enhancement of radioresponse of murine hepatocarcinoma when combined with radiation. The key element of enhancement is thought to be p21(WAF1/CIP1).
Seong
J
J
Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University Medical College, Seoul, Korea. jsseong@yumc.yonsei.ac.kr
Kim
S H
SH
Suh
C O
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D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D003131:Combined Modality Therapy; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology / Q000627:therapeutic use*; D011897:Random Allocation; D015854:Up-Regulation
D000970:Antineoplastic Agents; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D011838:Radiation-Sensitizing Agents