The Effect of Nerve Growth Factor and Antibodies to Nerve Growth Factor on Ethylnitrosourea-induced Neoplastic Proliferation in Rat Trigeminal Nerves

Sprague-Dawley (CD) rats were injected intravenously with ethylnitrosourea at a dose of 20 mg/kg on day 20 of gestation. This exposure resulted in early neoplastic proliferation or development of a neurinoma of the trigeminal nerve in 58% of the offspring at 90 days of age. Implantation of osmotic microinfusion pumps containing 2.5s nerve growth factor prior to ethylnitrosourea administration significantly reduced the incidence of early neoplastic proliferation. Postnatal implantation of microinfusion pumps containing 2.5s nerve growth factor also resulted in a significant but less pronounced reduction of early neoplastic proliferation. Immunoglobulin G directed against nerve growth factor (anti-nerve growth factor) did not influence the incidence of early neoplastic proliferation when administered via microinfusion pumps implanted on day 15 postnatally. These findings suggest that nerve growth factor has a protective effect on the developing nervous system against ethylnitrosourea-induced carcinogenesis. Resorptive nitrosourea derivatives have been used to induce neurogenic tumors in several species of ani- mals.I6 Rats are highly susceptible to development of neurogenic tumors after transplacental administration of ethylnitrosourea late in gestation. A single exposure of pregnant rats to 50 mg/kg of ethylnitrosourea on day 20 of gestation resulted in tumors of the nervous system in 100% of the off~pring.'~ Experiments on the sequen- tial development of these lesions indicated that the trigeminal nerve was one of the earliest and most con- sistently involved Sequential evaluations of the morphology, biochem- istry, and transplantability of trigeminal nerves from ethylnitrosourea-exposed rats from one day to six months of age2' revealed that histologic differences were present when comparing nerves of control and ethyl- nitrosourea-exposed rats by 20 days of age, in that 50% of nerves from the treated rats had hypercellularity, hyperchromatism, and increased numbers of mitotic figures. These changes occurred in the preganglionic segment, usually at or near the central nervous system- peripheral nervous system junction, and were accom- panied by a progressive increase in N-acetyl-p-glucosa- minidase and /3-glucuronidase activity to levels that were previously demonstrated in grossly visible neural t~rnors.~ Subcutaneous transplantation of nerves ex- posed to ethylnitrosourea into one-day-old syngeneic rats resulted in formation of neurinomas at the implan- tation site, while no tumors formed from transplanted nerves of controls. Based on these results, it was con- cluded that the morphologic changes seen represented an early neoplastic proliferation rather than a transient hyperplastic or preneoplastic tissue reaction to the car- cinogen. By 63 days of age, over 70% of the trigeminal nerves examined from ethylnitrosourea-exposed rats contained early neoplastic proliferation. Surprisingly, when the peak development of neurinomas would be expected at 182 days, only 30% of the nerves contained grossly visible neurinomas. It was not determined why relatively few of the nerves with early neoplastic prolif- eration progressed to visible tumors. The question re- mains as to what host factors influence tumor cell proliferation, regression, or both. Because immunologic mechanisms do not appear to influence neurogenic tumor f~rmation,~. 23 other host factors need to be eval- uated. From the general investigations of the influence that peripheral end organs have on their associated nerve centers came the discovery of nerve growth fac- e induction of differentiation and maturation of various in vitro and in vivo neuroecto- dermal tumors by nerve growth factor is well docu-