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1 Chin Med Biotechnol, December 2006, Vol. 1, No. 1 rmhtnf 64 2 rmhtnfrmhtnf mg/m 2 1~5 40 mg/m mg/m d 1 2 rmhtnf 1~7 11~17 rmhtnf 400 U/m 2 CR PR MR SD PD = CR+PR / 100%= CR+ PR+MR+SD / 100% KarnofskyWHO rmhtnf 17.5% 7/40 4.5% 1/22P=0.144 rmhtnf 80.0% 32/ % 12/22 P=0.036 rmhtnf Karnofsky 87.2± ±7.9 P =0.001 Karnofsky 84.1± ±7.8 Karnofsky P= 0.049rmhTNF rmhtnf rmhtnf, 2006, 1(1): TNF T [1] TNF rmhtnf TNF [2] rmhtnf [3-5] rmhtnf Karnofsky [6] /L /L 90 g/l 1 > ~ liu9503@126.com

2 Chin Med Biotechnol, December 2006, Vol. 1, No rmhtnf rmhtnf 2:1 rmhtnf rmhtnf 500 U/ ml:0.25g/ 10 mg/ 2 mg/ 500 mg/m 2 1~5 40 mg/m mg/m d 1 2 rmhtnf 1~7 11~17 rmhtnf 400 U/m CT 1 WHO CR 4 PR 50% 4 MR 25% 49%SD 25%25% PD 25% = (CR+PR)/ 100%=(CR+PR+ MR+SD)/ 100% Karnofsky [6] WHO SPSS 11.0 χ 2 t rmhtnf rmhtnf 17.5% 7/40 4.5% 1/22 P=0.144 rmhtnf 80.0% 32/ % 12/22 P= Karnofsky P=0.606 rmhtnf Karnofsky [ % ] Table 1 The clinical stage and previous therapy of the patients with advanced gastric cancers in the two groups [No. of cases (%)] Clinical stage Previous therapy Cases Stage Stage Operation Chemotherapy rmhtnf rmhtnf group Chemotherapy group χ 2 χ 2 value P P value

3 Chin Med Biotechnol, December 2006, Vol. 1, No. 1 P=0.001P=0.665 rmhtnf Karnofsky P= rmhtnf rmhtnf TNF [1, 7] TNF [1] [1] [1] [8] [1] TNF TNF [ % ] Table 2 Response and clinical benefit rates of the patients with advanced gastric cancer in the two groups [No. of cases (%)] Cases PR MR SD PD Clinical benefit rmhtnf rmhtnf Group 40 7(17.5)* 8(20.0) 17(42.5) 8(20.0) 32(80.0) Chemotherapy Group 22 1(4.5) 3(13.6) 8(36.4) 10(45.5) 12(54.5) CRPR PR (MR) (SD)* χ² P χ² P Note: (1) There was no case with complete response (CR), so the rate of partial response (PR) is response rate. (2) PR minimal response (MR) stable disease (SD) was defined as clinical benefit rate. *compared with chemotherapy group, χ² 2.449, P 0.144; compared with chemotherapy group, χ² 4.392, P Karnofsky x ± s Table 3 Karnofsky scores of the patients with advanced gastric cancer in the two groups before and after treatment x ± s Cases Before treatment After treatment t t value P P value rmhtnf rmhtnf group ± ± Chemotherapy Group ± ± t t value P P value Table 4 Adverse reactions of the patients with advanced gastric cancer in the two groups during treatment No. of cases rmhtnf rmhtnf group Chemotherapy group P (n=40) (n=24) Adverse reactions P value 0 0 Anemia Leukopenia Thrombocytopia Nausea / Vomiting Fever Eruption Cold-like symptoms Ostealgia / Myosalgia Chill Pain in injection area Hardening, swelling and redness in injection area Note: 0,, and represent the degree of adverse reactions. No patient presented with IV-degree adverse reaction.

4 Chin Med Biotechnol, December 2006, Vol. 1, No TNF TNF TNF [2, 8-11] Nakamura [10] htnf-α N 7 Arg-Lys-Arg htnf-α Pro 8 Ser 9 Asp 10 htnf-α Mutant471 Mutant471 htnf-α 7 Kamijo [11] htnf-α 157 Leu Phe htnf-α htnf-α 20 rmhtnf htnf-αn 7 13 Arg-Lys-Arg htnf-α Leu Phe [2] [12] rmhtnf S180 H22 B16 Lewis TNF-α rmhtnf 94.1% 32/3489.4% 42/47 [4, 5] [3] rmhtnf 46.9% 68/ rmhtnf % CR PR [13] rmhtnf 17.5% 4.5% P=0.144 rmhtnf 80.0% 54.5% P= rmhtnf Karnofsky P=0.001 P=0.665rmhTNF KarnofskyP= TNF [7] rmhtnf rmhtnf TNF [1, 8, 14] rmhtnf 75.0% 30/ % 19/ % 19/ % 18/40 3~5 25 mg rmhtnf rmhtnf rmhtnf [1] Lee KY, Chang W, Qiu D, et al. PG 490 (triptolide) cooperates with tumor necrosis factor-alpha to induce apoptosis in tumor cells. J Biol Chem, 1999, 274(19): [2] Zhang YQ, Zhao N, Li B, et al. Preparation of a novel recombinant human tumor necrosis factor-αby gene engineering technology. Chin J Cell Mol Immunol, 2002, 18(4): (in Chinese),,,. -α., 2002, 18(4): [3] Zhou QH, Yan X, Ren L, et al. A multicenter randomized phase trial of domestic product of rmhtnf in the treatment of non-small cell lung cancer. Chin J Lung Cancer, 2003, 6(4): (in Chinese),,,.., 2003, 6(4): [4] Wei D, Su XM, Liu HY, et al. The effect of pericardial antrum perfused with recombination mutant human tumor necrosis factor onmalignant pericardial effusion. Chin J Oncol, 2006, 28(1):75. (in Chinese),,,.., 2006, 28(1):75. [5] Yang YJ, Yuan ZJ, Luo Y, et al. Clinical experiment about treating the malignant pleural or peritoneal pericardial effusion with recombination mutant human tumor necrosis factor. China Oncology, 2004, 14(4): (in Chinese),,,. 47., 2004, 14(4): [6] Karnofsky DA, Burchenal JH. The clinical evaluation of chemotherapeutic agents in cancer//macelod CM. Evaluation of chemotherapeutic agents. New York: Columbia University Press,1994: [7] Nakamoto T, Inagawa H, Takagi K, et al. A new method of antitumor therapy with a high dose of TNF perfusion for unresectable liver tumors. Anticancer Res, 2000, 20 (6A): [8] Lasek W, Giermasz A, Kuc K, et al. Potentiation of the anti-tumor effect of actinomycin D by tumor necrosis factor alpha in mice:

5 Chin Med Biotechnol, December 2006, Vol. 1, No. 1 correlation between in vitro and in vivo results. Int J Cancer, 1996, 66(3): [9] Gase K, Korobko VG, Wisniewski HG, et al.critical role of the C- terminus in the biological activities of human tumor necrosis factoralpha. Immunology, 1990, 71(3): [10] Nakamura S, Kato A, Masegi T, et al. A novel recombinant tumor necrosis factor-alpha mutant with increased anti-tumor activity and lower toxicity. Int J Cancer, 1991, 48(5): [11] Kamijo R, Takeda K, Nagumo M, et al. Induction of differentiation of human monoblastic and myeloblastic leukemia cell lines by TNF muteins. Biochem Biophys Res Commun, 1989, 160(2): [12] Zhao N, Zhang YQ, Wang ZL. Preclinical study of a novel recombinant human tumor necrosis factor-α. Chin J Cell Mol Immunol, 2002, 18(2): (in Chinese),,. -α., 2002, 18(2): [13] Liu X, Zhang XF, Zheng ZW, et al. The effect of chemotherapy combined with recombination mutant human tumor necrosis factor on advanced cancer. Chin-Germ J Clin Oncol, 2005, 4(3): [14] Schilling PJ, Murray JL, Markowitz AB. Novel tumor necrosis factor toxic effects. Pulmonary hemorrhage and severe hepatic dysfunction. Cancer, 1992, 69(1): Effect of recombinant mutant human tumor necrosis factor on advanced gastric cancer: randomized controlled study LIU Xing, ZHANG Xiang-fu, LU Hui-shan, WU Xin-yuan, HUANG Chang-ming, WANG Chuan, GUAN Guo-xian Abstract Objective To observe the therapeutic effect of recombinant mutant human tumor necrosis factor (rmhtnf) combined with general chemotherapy on advanced gastric cancer, and to investigate the toxicity of rmhtnf. Methods A prospective randomized case-controlled study, in which 64 patients with advanced gastric cancer were recruited, was carried out. The patients were randomly divided into rmhtnf (40 patients) and chemotherapy groups (24 patients). Both the groups received chemotherapy consisting of two 21-day cycles of 5-FU 500 mg/ m 2 (day 1 5), ADM 40 mg/ m 2 (day 1), and MMC 6 mg/ m 2 (day 1). During the chemotherapy, rmhtnf ( U/m 2 ) was given to the rmhtnf group by injection from the 1st to 7th day, and the 11th to 17th day. According to the WHO criteria, the clinical response was classified as complete response (CR), partial response (PR), minimal response (MR), stable disease (SD), and progression disease (PD). The response rate (CR+PR) and clinical benefit rate (CR+PR+MR+SD) were calculated. The toxicity of rmhtnf was graded using the WHO scale for acute and subacute toxicity. Results Of the 64 patients, 2 in the chemotherapy group dropped out of the trial, the outcomes of other 62 patients were evaluated. In the rmhtnf group, 7 patients achieved PR, the response rate was 17.5% (7/40), which was higher than that in the chemotherapy group [4.5% (1/22)], but without significant difference (P=0.144). The clinical benefit rate in the rmhtnf group was significantly higher than that in the chemotherapy group [80.0% (8/17) vs. 54.5% (12/22), P=0.036]. In the rmhtnf group, the Karnofsky score increased significantly after the treatment (after treatment 87.2±7.5 vs. before treatment 83.0±8.0, P=0.001), whereas it did not changed significantly in the chemotherapy group (84.1±8.0 vs. 83.2±7.8, P>0.05). The Karnofsky score after the treatment in the rmhtnf group was significantly higher than that in the chemotherapy group (P=0.049). The toxicity of the rmhtnf was evaluated in all the 64 patients. The most frequent adverse reactions to rmhtnf included pain, hardening, swelling, and redness at the site of injection, chill, ostealgia and myosalgia, fever, and cold-like symptoms, all of which were mild and tolerable. Conclusions Chemotherapy combined with rmhtnf can improve the short-term outcomes, health status, and quality of life of patients with advanced gastric cancer. The adverse reactions to the local injection of rmhtnf are mild and tolerable. Key words Stomach neoplasms; Adenocarcinoma; Tumor necrosis factors; Biological therapy; Drugtherapy Author Affiliation: Department of Oncology, Union Hospital of Fujian Medical University, Fuzhou , China Corresponding Author: LIU Xing, liu9503@126.com Chin Med Biotech, 2006, 1(1):46-50