Brandes L J, Warrington R C, Arron R J, Bogdanovic R P, Fang W, Queen G M, Stein D A, Tong J, Zaborniak C L, LaBella F S
Department of Medicine, Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Canada.
J Natl Cancer Inst. 1994 May 18;86(10):770-5. doi: 10.1093/jnci/86.10.770.
Present studies of drug-induced tumor growth promotion have evolved from earlier investigations into the mechanism of action of N,N-diethyl-2-[4-(phenylmethyl)phenoxy[ethanamine.HCl, a tamoxifen derivative which potently inhibits lymphocyte mitogenesis in vitro and stimulates tumor growth in vivo. It is thought that potency to bind to intracellular histamine receptors (HIC), some of which are on cytochromes P450, may correlate with tumor growth-promoting activity.
We assessed the effectiveness of five in vitro assays in predicting in vivo tumor growth stimulation by the H1-antihistamines loratadine, astemizole, cetirizine, hydroxyzine, and doxylamine.
Potency of each agent was ranked 1-5 in each of the following in vitro assays: 1) inhibition of [3H]histamine binding to microsomal HIC, 2) inhibition of histamine binding to microsomal P450, 3) inhibition of the P450-catalyzed demethylation of aminopyrine, 4) inhibition of lymphocyte mitogenesis, and 5) stimulation of tumor colony formation. An overall rank score was assigned to each drug and correlated with tumor growth stimulation in vivo. Two laboratories conducted in vivo studies in a blinded fashion. Female C57BL and C3H mice were given a subcutaneous injection on day 1 of syngeneic B16F10 melanoma cells (5 x 10(5)) or C-3 fibrosarcoma cells (1 x 10(5)), respectively. Mice were randomly assigned to treatment groups, then received a single, daily intraperitoneal injection of an estimated human-equivalent dose (or range of doses) of antihistamine or vehicle control for 18-21 days before being killed. Tumors were surgically removed and wet weights compared statistically among groups.
The cumulative potency of each drug in affecting tumor growth or growth mechanisms in the five in vitro assays ranked as follows: Loratidine and astemizole ranked highest and were equally potent, followed in decreasing order by hydroxyzine, doxylamine, and cetirizine. A significant correlation (r = .97; P < .02) was observed between the rank order of potency of the antihistamines in all five in vitro assays and the rank order to enhance tumor growth in vivo: Loratidine and astemizole significantly (P < .001) promoted the growth of both melanoma and fibrosarcoma, hydroxyzine significantly (P < .001) promoted the growth of melanoma, while doxylamine and cetirizine did not promote the growth of either tumor.
Data demonstrate that the in vitro assays predicted the propensity of each H1-antihistamine to stimulate cancer growth in vivo.
These in vitro tests may prove valuable to screen potential tumor growth promoters.
目前关于药物诱导肿瘤生长促进作用的研究是从早期对N，N - 二乙基 - 2 - [4 -（苯甲基）苯氧基]乙胺盐酸盐作用机制的研究发展而来的，它是一种他莫昔芬衍生物，在体外能有效抑制淋巴细胞有丝分裂，在体内能刺激肿瘤生长。据认为，与细胞内组胺受体（HIC）结合的能力，其中一些位于细胞色素P450上，可能与肿瘤生长促进活性相关。
我们评估了五种体外试验预测H1 - 抗组胺药氯雷他定、阿司咪唑、西替利嗪、羟嗪和多西拉敏在体内刺激肿瘤生长的有效性。
在以下每种体外试验中，将每种药物的效力从1到5进行排名：1）抑制[3H]组胺与微粒体HIC的结合；2）抑制组胺与微粒体P450的结合；3）抑制P450催化的氨基比林脱甲基作用；4）抑制淋巴细胞有丝分裂；5）刺激肿瘤集落形成。为每种药物分配一个总体排名分数，并将其与体内肿瘤生长刺激相关联。两个实验室以盲法进行体内研究。雌性C57BL和C3H小鼠分别在第1天皮下注射同基因B16F10黑色素瘤细胞（5×10⁵）或C - 3纤维肉瘤细胞（1×10⁵）。小鼠被随机分配到治疗组，然后在处死前18 - 21天每天腹腔注射一次估计的人等效剂量（或剂量范围）的抗组胺药或载体对照。手术切除肿瘤并对各组肿瘤的湿重进行统计学比较。
在五种体外试验中，每种药物影响肿瘤生长或生长机制的累积效力排名如下：氯雷他定和阿司咪唑排名最高且效力相当，其次依次为羟嗪、多西拉敏和西替利嗪。在所有五种体外试验中抗组胺药的效力排名顺序与体内增强肿瘤生长的排名顺序之间观察到显著相关性（r = 0.97；P < 0.02）：氯雷他定和阿司咪唑显著（P < 0.001）促进黑色素瘤和纤维肉瘤的生长，羟嗪显著（P < 0.001）促进黑色素瘤的生长，而多西拉敏和西替利嗪均未促进两种肿瘤的生长。
数据表明体外试验预测了每种H1 - 抗组胺药在体内刺激癌症生长的倾向。
这些体外试验可能被证明对筛选潜在的肿瘤生长促进剂有价值。
