In vivo pharmacology and anti-tumour evaluation of the tyrphostin tyrosine kinase inhibitor RG13022.
In vivo pharmacology and anti-tumour evaluation of the tyrphostin tyrosine kinase inhibitor RG13022.
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DOI：
10.1038/bjc.1996.620
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发表时间：
1996-12
影响因子：
8.8
通讯作者：
Graham, M A
中科院分区：
文献类型：
--
作者：
McLeod, H L;Brunton, V G;Eckardt, N;Lear, M J;Robins, D J;Workman, P;Graham, M A
在人类肿瘤中已经观察到许多生长因子受体的扩增和表达增加，包括表皮生长因子受体(EGFR)。一种克服EGF自分泌控制肿瘤生长的治疗策略是抑制EGFR蛋白酪氨酸激酶(PTK)。目前已鉴定出一系列小分子在体外对EGFR PTK具有抑制作用，并对高表达EGFR的人癌细胞具有抗增殖活性。据报道，其中一种化合物tyrphostin RG13022在鳞癌异种移植瘤中有显著的生长延迟。基于这些令人鼓舞的结果，我们试图证实RG13022在体内的活性，并将其影响与体内血浆处置联系起来。MF1nu/nu小鼠腹腔注射RG13022 20 mg·kg~(-1)后，用高效液相色谱法检测到RG13022和另外3个峰。RG13022在血浆中表现出快速的双指数消除，末端半衰期为50.4分钟。注射后20min，RG13022血药浓度均小于1微米。初步产物为几何异构体(E)-RG13022。RG13022及其几何异构体对体外培养的HN5细胞的DNA合成均有抑制作用(IC50分别为11微米和38微米)。RG13022及其几何异构体均未表现出明显的细胞毒性。RG13022在肿瘤接种当天或肿瘤异种移植建立后开始长期给药，对HN5肿瘤的生长没有影响。RG13022的体内快速消除对该药物和其他相关酪氨酸激酶抑制剂的开发具有潜在的意义，因为在注射后20分钟，RG13022的血浆浓度降至体外活性所需的水平以下。体内肿瘤生长延迟的缺乏表明RG13022更理想的给药方案将包括更频繁的注射或连续给药。因此，在进一步开发这种或其他类似的蛋白酪氨酸激酶抑制剂之前，需要改进RG13022的配方。还应寻求替代策略，以显示更长时间的体内暴露。
Amplification and increased expression of many growth factor receptors, including the epidermal growth factor receptor (EGFR), has been observed in human tumours. One therapeutic strategy for overcoming EGF autocrine control of tumour growth is inhibition of EGFR protein tyrosine kinase (PTK). A series of low molecular weight molecules have been identified which inhibit the EGFR PTK in vitro and demonstrate antiproliferative activity against human cancer cell lines with high expression of EGFR. A significant growth delay in squamous cancer xenografts has been reported for one of these compounds, the tyrphostin RG13022. Based on these encouraging results, we sought to confirm the activity of RG13022 in vivo and relate the effects to the in vivo plasma disposition. RG13022 and three additional peaks were detected by HPLC following intraperitoneal administration of 20 mg kg-1 RG13022 in MF1 nu/nu mice. RG13022 demonstrated rapid biexponential elimination from plasma with a terminal half-life of 50.4 min. RG13022 plasma concentrations were less than 1 microM by 20 min post injection. A primary product was identified as the geometrical isomer (E)-RG13022. Both RG13022 and its geometrical isomer inhibited DNA synthesis in HN5 cells after a 24 h in vitro incubation (IC50 = 11 microM and 38 microM respectively). Neither RG13022 nor its geometrical isomer displayed significant cytotoxicity. RG13022 had no influence on the growth of HN5 tumours when administered chronically, starting either on the day of tumour inoculation or after establishment of tumour xenografts. The rapid in vivo elimination of RG13022 has potential significance to the development of this and other related tyrphostin tyrosine kinase inhibitors, as plasma concentrations fell below that required for in vitro activity by 20 min post injection. The lack of in vivo tumour growth delay suggests that a more optimal administration schedule for RG13022 would include more frequent injections or continuous administration. An improved formulation for RG13022 is therefore required before further development of this or other similar protein tyrosine kinase inhibitors can be made. Alternative strategies should also be sought which display longer lasting in vivo exposures.