ハーセプチン添付文書に以下の記述があります。
| HER2高発現のヌードマウス可移植性ヒト乳癌（MCF7-HER2、BT-474（細胞当たりのHER2レセプター数＝1.0×106））及びヒト胃癌（NCI-N87）に対し抗腫瘍効果が認められた30）-32）。 |
この記述の根拠となった文献がこちら。
30）Pietras RJ, et al. Oncogene. 1998;17:2235-49.
31）Baselga J, et al. Cancer Res. 1998;58:2825-31.
32）Fujimoto-Ouchi K, et al. Cancer Chemother Pharmacol. 2007;59:795-805.
PubMedで検索すればすぐに見つかります。
今日は以下のAbstractをイートモ用に対訳化して終わり。
Remission of human breast cancer xenografts on therapy with humanized monoclonal antibody to HER-2 receptor and DNA-reactive drugs
R J Pietras 1, M D Pegram, R S Finn, D A Maneval, D J Slamon
Affiliations expand
PMID: 9811454 DOI: 10.1038/sj.onc.1202132
Abstract
HER-2 oncogene encodes a transmembrane growth factor receptor that is overexpressed in 25-30% of patients with primary breast and ovarian cancer. A murine monoclonal antibody, 4D5, to the extracellular domain of HER-2 receptor elicits cytostatic growth inhibition of tumor cells overexpressing HER-2 protein, but clinical use of this antibody is limited by genesis of human anti-mouse antibodies. To avoid this problem, a recombinant humanized 4D5 monoclonal antibody (rhuMAb HER-2) was developed and tested using a human tumor xenograft model. Human breast and ovarian cancer cells which overexpress HER-2 were inhibited in vivo by the rhuMAb HER-2 antibody. Tumor growth relative to control was reduced at all doses of antibody tested, and the magnitude of growth inhibition was directly related to dose of rhuMAb HER-2. Tumor growth resumed on termination of antibody therapy, indicating a cytostatic effect. To elicit a cytotoxic response, human breast tumor xenografts were treated with a combination of antibody and antitumor drugs, cisplatin or doxorubicin. The combination of antibody with either cisplatin or doxorubicin resulted in significantly greater growth inhibition, with the cisplatin combination demonstrating a greater response. In addition, therapy with cisplatin and antireceptor antibody elicited complete tumor remissions after 2-3 cycles of therapy. The schedule of administration of anti-receptor antibody and cisplatin was critical for occurrence of antibody-induced potentiation in cisplatin cytotoxicity. Enhanced killing of tumor cells was found only if antibody and drug were given in close temporal proximity. Since interference with DNA repair pathways may contribute to this receptor-enhanced chemosensitivity, repair of cisplatin-damaged reporter DNA (pCMV-beta) was determined in human breast cells. As in studies of antibody-enhanced cisplatin cytotoxicity in vivo, treatment with rhuMAb HER-2 blocked the repair of cisplatin-damaged DNA only if the antibody was administered in close temporal proximity to transfection of the drug-exposed reporter DNA. An alternative measure of DNA repair, unscheduled DNA synthesis, was also assessed. Treatment with either cisplatin or doxorubicin led to an increase in unscheduled DNA synthesis that was reduced by combined therapy with antireceptor antibody specific to HER-2-overexpressing breast cancer cells. Using a direct measure of DNA repair, therapy of HER-2-overexpressing cells with rhuMAb HER-2 also blocked the removal of cisplatin-induced DNA adducts. Expression of p21/WAF1, an important mediator of DNA repair, was disrupted in breast cancer cells with HER-2 overexpression, but not in control cells, after treatment with HER-2 antibody, thus suggesting cross-communication between the HER-2 signaling and DNA repair pathways. These data demonstrate an in vivo antiproliferative effect of rhuMAb HER-2 on tumors that overexpress HER-2 receptor and a therapeutic advantage in the administration of the antireceptor antibody in combination with chemotherapeutic agents.
Recombinant humanized anti-HER2 antibody (Herceptin) enhances the antitumor activity of paclitaxel and doxorubicin against HER2/neu overexpressing human breast cancer xenografts
J Baselga 1, L Norton, J Albanell, Y M Kim, J Mendelsohn
Affiliations expand
PMID: 9661897
Free article
Erratum in
Cancer Res 1999 Apr 15;59(8):2020
Abstract
Recombinant humanized anti-HER2 antibody, rhuMAb HER2, inhibits the growth of breast cancer cells overexpressing HER2 and has clinical activity. We explored in preclinical models its capacity to enhance the tumoricidal effects of paclitaxel and doxorubicin. In cultures of naturally HER2-overexpressing cancer cells, rhuMAb HER2 inhibited growth and enhanced the cytotoxic effects of paclitaxel. Treatment of well established BT-474 breast cancer xenografts overexpressing HER2 in athymic mice with rhuMAb HER2 resulted in a dose-dependent antitumor activity. In combination studies, treatment with paclitaxel and rhuMAb HER2 or doxorubicin and rhuMAb HER2 resulted in greater inhibition of growth than that observed with any agent alone. The combination of paclitaxel and rhuMAb HER2 resulted in the highest tumor growth inhibition and had a significantly superior complete tumor regression rate when compared with either paclitaxel or rhuMAb HER2 alone. Clinical trials that are built on these results are under way.
Antitumor activity of trastuzumab in combination with chemotherapy in human gastric cancer xenograft models
Kaori Fujimoto-Ouchi 1, Fumiko Sekiguchi, Hideyuki Yasuno, Yoichiro Moriya, Kazushige Mori, Yutaka Tanaka
Affiliations expand
PMID: 17031648 DOI: 10.1007/s00280-006-0337-z
Abstract
Purpose: To clarify the antitumor activity of trastuzumab and its potential as an effective treatment for gastric cancer patients.
Methods: Levels of HER2 expression in tumor tissues of gastric cancer cell lines were examined using immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and mRNA quantification. Efficacy of trastuzumab was examined as a single agent or in combination with chemotherapeutic agents widely used clinically for gastric cancers in HER2-overexpressing human gastric cancer xenograft models.
Results: Two of nine human gastric cancer xenograft models, NCI-N87 and 4-1ST, showed overexpression of HER2 mRNA and protein by IHC (HercepTest) and HER2 gene amplification by FISH (Pathvysion). HER2 protein showed potent staining in peripheral membranes, similar to the staining pattern of breast cancer. FISH scores were also comparable to those of breast cancer models. Trastuzumab as a single agent inhibited the tumor growth in both of the HER2-overexpressing models but not in the HER2-negative models, GXF97 and MKN-45. In any combination with capecitabine, cisplatin, irinotecan, docetaxel, or paclitaxel, trastuzumab showed more potent antitumor activity than the anticancer agents alone. A three-drug combination of capecitabine, cisplatin, and trastuzumab showed remarkable tumor growth inhibition. In NCI-N87 in vitro, trastuzumab showed direct antiproliferative activity according to cell count or crystal violet dying, and showed indirect antitumor activity such as antibody-dependent cellular cytotoxicity.
Conclusion: The antitumor activity of trastuzumab observed in human gastric cancer models warrants consideration of its use in clinical treatment regimens for human gastric cancer as a single agent or a combination drug with various chemotherapeutic agents.
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