rg-13022 and Carcinoma--Squamous-Cell

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.

Topics: Animals; Antineoplastic Agents; Carcinoma, Squamous Cell; Chromatography, High Pressure Liquid; Drug Screening Assays, Antitumor; Female; Humans; Mice; Mice, Nude; Nitriles; Protein-Tyrosine Kinases; Pyridines; Transplantation, Heterologous; Tumor Cells, Cultured; Tyrphostins

Many human tumors of epithelial origin contain cells overexpressing the epidermal growth factor (EGF) receptor, and there is convincing evidence that cancer cell growth is correlated with the loss of the normal regulation of the EGF receptor signal transduction pathway. Some cancers are clearly dependent on activation of the EGF receptor for their proliferation. Recently, a class of compounds, tyrphostins, which inhibit the protein tyrosine kinase activity of the growth factor receptor, have been described. In this report, we have examined the antiproliferative effects of potent new tyrphostins on a well-characterized human squamous cell carcinoma in vitro and in vivo. We found that two of these compounds (RG-13022 and RG-14620) suppressed not only EGF-stimulated cancer cell proliferation in vitro but also tumor growth in nude mice. RG-13022 also increased the life span of these tumor-bearing nude mice. When administered to tumor-bearing nude mice together with monoclonal antibodies to the EGF receptor at a suboptimal dose which had no effect alone, inhibition of tumor growth was markedly enhanced. These data suggest that tyrphostins have potential as anticancer agents.

Topics: Animals; Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Line; ErbB Receptors; Humans; Kinetics; Maxillary Neoplasms; Mice; Mice, Nude; Neoplasm Transplantation; Nitriles; Phosphorylation; Protein-Tyrosine Kinases; Pyridines; Transfection; Transplantation, Heterologous; Tyrphostins