Epidermal growth factor-responsive and -refractory carcinomas initiated with N-methyl-N-nitrosourea in rat urinary bladder.

We tested the role of epidermal growth factor (EGF) in the development of low-grade superficial bladder tumors by using a heterotopically transplanted rat urinary bladder system. Weekly EGF administration (250 ng/0.5 ml of phosphate-buffered 2.1% NaCl solution) for 28 weeks into heterotopically transplanted rat urinary bladders initiated with a low dose of N-methyl-N-nitrosourea resulted in a significant increase in the incidence (17 of 25 versus 6 of 30 rats; P < 0.001) and the mean number of tumors per bladder (1.08 versus 0.20; P < 0.001) as compared with those for a vehicle-only group. Changing to vehicle without EGF for the last 8 weeks resulted in tumors in 8 of 24 rats (P = 0.02 versus the EGF group), comparable to the rate for controls. Switching from vehicle to EGF for the last 8 weeks resulted in tumors in 15 of 24 rats, comparable to the rate in the 28-week EGF group. When tumors were divided into two groups according to size (>4.2 mm3 and </= 4.2 mm3), expression of EGF receptor (EGF-R) was found in 24 of 25 "large" tumors as compared with 5 of 17 "small" tumors (P < 0.0001). The results of in situ hybridization for EGF-R correlated well with those of immunohistochemical study. These data suggest the possibility that recurrences of low-grade superficial bladder tumors are related to the continuing presence of EGF in the urine, and that blocking of EGF-R should be evaluated as a tumor inhibitor.