The antiproliferative effects of tyrosine kinase inhibitors tyrphostins on a human squamous cell carcinoma in vitro and in nude mice.
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.
Yoneda
T
T
Department of Medicine, University of Texas Health Science Center, San Antonio 78284-7877.
Lyall
R M
RM
Alsina
M M
MM
Persons
P E
PE
Spada
A P
AP
Levitzki
A
A
Zilberstein
A
A
Mundy
G R
GR
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D002460:Cell Line; D066246:ErbB Receptors / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008441:Maxillary Neoplasms / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009570:Nitriles / Q000494:pharmacology* / Q000627:therapeutic use; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D014162:Transfection; D014183:Transplantation, Heterologous; D020032:Tyrphostins
D000970:Antineoplastic Agents; D009570:Nitriles; D011725:Pyridines; D020032:Tyrphostins; C070274:RG 13022; C070273:RG 14620; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases