Baselga J, Norton L, Masui H, Pandiella A, Coplan K, Miller W H, Mendelsohn J
Department of Medicine, Cornell University Medical College, New York, N.Y.
J Natl Cancer Inst. 1993 Aug 18;85(16):1327-33. doi: 10.1093/jnci/85.16.1327.
A variety of human tumors frequently express high levels of epidermal growth factor (EGF) receptor and its ligand, transforming growth factor alpha (TGF-alpha), which in some tumors is associated with poor prognosis. Monoclonal antibodies (MAbs) that block the binding of TGF-alpha or EGF to the receptor can inhibit proliferation of tumor cells that express the receptor. Studies suggest that these MAbs may enhance the antitumor effects of chemotherapy.
Our purpose was to study, in vitro and in vivo, the antitumor effects of doxorubicin in combination with anti-EGF receptor MAbs against tumor cells expressing high levels of EGF receptor. Our goal was to achieve maximum initial cytoreduction with high-dose doxorubicin in association with prolonged blockade of EGF receptor with MAbs.
Anti-EGF receptor MAbs 528 (isotype IgG2a) and 225 (isotype IgG1) were used in combination with doxorubicin against cells from human A431 squamous cell carcinoma and human MDA-468 breast adenocarcinoma. Both A431 and MDA-468 cells express high levels of EGF receptors and TGF-alpha. Cultured cells were treated with doxorubicin (range, 0-10 nM) in the presence or absence of MAb 528 or 225 (range, 0-30 nM). At 48 hours, doxorubicin-containing medium was removed, and treatment with antibody was continued for 5 days, when cell proliferation assays were performed. The activity of the agents and the combinations against well-established xenografts in BALB/c nude mice was also studied. In nude mice, doxorubicin was given at doses of 50-100 micrograms/20 g body weight on 2 successive days, and MAbs 528 and 225 were given at a dose range of 0-2 mg intraperitoneally twice a week.
MAbs 528 and 225 both enhanced the antitumor effects of doxorubicin against A431 and MDA-468 tumor cells, producing additive growth suppression in cell cultures. MAb 528 increased the antitumor effects of doxorubicin by 32%-42%, and similar results were obtained with MAb 225. In BALB/c athymic mice, the treatment of well-established xenografts with either doxorubicin or anti-EGF receptor MAb alone temporarily inhibited growth, but the combination of both agents substantially enhanced antitumor activity over that of doxorubicin alone in A431 and MDA-468 cell xenografts. The combination treatment of mice bearing A431 xenografts resulted in tumor eradication of 40%-100% in the surviving mice in several independent experiments. The enhanced antitumor activity was dose dependent.
Our results suggest that anti-EGF receptor MAbs substantially enhance the effects of doxorubicin against well-established xenografts of tumor cells expressing high levels of EGF receptors.
Clinical trials with anti-EGF receptor MAbs are being conducted, and trials with anti-EGF receptor MAbs combined with doxorubicin are planned.
多种人类肿瘤常常高表达表皮生长因子（EGF）受体及其配体转化生长因子α（TGF-α），在某些肿瘤中这与预后不良相关。阻断TGF-α或EGF与受体结合的单克隆抗体（MAb）可抑制表达该受体的肿瘤细胞增殖。研究表明这些单克隆抗体可能增强化疗的抗肿瘤作用。
我们旨在体外和体内研究阿霉素联合抗EGF受体单克隆抗体对高表达EGF受体的肿瘤细胞的抗肿瘤作用。我们的目标是用高剂量阿霉素实现最大程度的初始细胞减灭，并通过单克隆抗体延长对EGF受体的阻断。
抗EGF受体单克隆抗体528（同种型IgG2a）和225（同种型IgG1）与阿霉素联合用于处理人A431鳞状细胞癌和人MDA - 468乳腺腺癌的细胞。A431和MDA - 468细胞均高表达EGF受体和TGF-α。培养的细胞在有或无单克隆抗体528或225（浓度范围0 - 30 nM）存在的情况下用阿霉素（浓度范围0 - 10 nM）处理。48小时后，去除含阿霉素的培养基，继续用抗体处理5天，然后进行细胞增殖测定。还研究了这些药物及其组合对BALB/c裸鼠中已建立的异种移植物的活性。在裸鼠中，连续2天给予阿霉素，剂量为50 - 100微克/20克体重，单克隆抗体528和225腹腔注射，剂量范围为0 - 2毫克，每周2次。
单克隆抗体528和225均增强了阿霉素对A431和MDA - 468肿瘤细胞的抗肿瘤作用，在细胞培养中产生相加的生长抑制作用。单克隆抗体528使阿霉素的抗肿瘤作用增强了32% - 42%，单克隆抗体225也得到了类似结果。在BALB/c无胸腺小鼠中，单独用阿霉素或抗EGF受体单克隆抗体处理已建立的异种移植物可暂时抑制生长，但两种药物联合使用在A431和MDA - 468细胞异种移植物中比单独使用阿霉素显著增强了抗肿瘤活性。在几个独立实验中，对携带A431异种移植物的小鼠进行联合治疗，使存活小鼠中的肿瘤根除率达到40% - 100%。增强的抗肿瘤活性呈剂量依赖性。
我们的结果表明，抗EGF受体单克隆抗体可显著增强阿霉素对高表达EGF受体的肿瘤细胞已建立的异种移植物的作用。
正在进行抗EGF受体单克隆抗体临床试验，并计划开展抗EGF受体单克隆抗体联合阿霉素的试验。
