Epidermal growth factor receptor-mediated selective cytotoxicity of antitumor agents toward human xenografts and murine syngeneic solid tumors.
Severe toxic side effects of antiproliferative agents limit their clinical usefulness as antitumor drugs. Recently we observed that the antitumor efficacy of various antitumor agents (5-fluorouracil, tegafur, adriamycin, mitomycin C, cyclophosphamide, and cisplatin) against experimental solid tumors was enhanced by prior or simultaneous administration of human epidermal growth factor (EGF). However, coadministration of EGF did not enhance the toxicity of antitumor agents as measured by LD50 and body weight loss. The above selective potentiation of efficacy of the antitumor agents by human EGF can be characterized as follows. In a dose-dependent manner, human EGF enhanced the efficacy of an antitumor agent (5-FU) treatment against human epidermoid carcinoma A431 transplanted sc in athymic nude mice [ED50 = 2.9 (0.2-49.7, 95% confidence interval) microgram/kg, sc]. Various degrees of enhancement were also observed against other experimental tumors transplanted sc. The degrees of enhancement were directly proportional to the numbers of human EGF binding sites present on tumor cell plasma membrane (threshold of binding site density = 1.5 X 10(3) sites/cell) using 5-FU or cisplatin as an antitumor agent, thus suggesting that the binding of EGF to the receptors on tumor cells is an essential process in enhancing the susceptibility of tumor cells to antitumor agents. Normal cells including intestinal epithelial and bone marrow cells are endowed with fewer EGF binding sites (less than 10(3) sites/cell). This may explain partially the absence of EGF-enhanced cytotoxicity by antitumor agents toward normal cells.
Amagase
H
H
Institute for Medical Research, Wakunaga Pharmaceutical Co., Ltd., Hiroshima.
Kakimoto
M
M
Hashimoto
K
K
Fuwa
T
T
Tsukagoshi
S
S
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004815:Epidermal Growth Factor / Q000008:administration & dosage*; D066246:ErbB Receptors / Q000502:physiology*; D005472:Fluorouracil / Q000008:administration & dosage / Q000633:toxicity; D006801:Humans; D007928:Lethal Dose 50; D051379:Mice; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D013997:Time Factors
D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D002945:Cisplatin; D005472:Fluorouracil