Sarah E. Stewart

The induction of neoplasms with a substance released from mouse tumors by tissue culture

Abstract Evidence suggesting replication of a subcellular tumor-inducing substance in mouse parotid gland neoplasms and mouse leukemias was obtained by culturing preparations from these tumors on monkey kidney and chick chorioallantoic membrane cells in vitro. Unlike the results obtained by Stewart (1953, 1955a, b) with mouse leukemia cell-free extracts, newborn mice injected with cell-free inocula prepared from 20 parotid gland tumors have not developed neoplasms, even after life spans in some instances of more than 2 years. However, when preparations from some of the same tumors were put into tissue cultures and newborn mice were inoculated with the supernatant fluids from these cultures, many developed multiple primary tumors. Mice inoculated with fluids from tissue cultures that had not received the tumor cells failed to develop these neoplasms. All the mice that developed neoplasms had both parotid gland tumors and multiple proliferative renal lesions involving the convoluted tubules. In addition, one or more of the following were observed as primary neoplasms in both sexes: tumors of the submaxillary, sublingual and the exorbital lacrimal glands, thymic epithelioid tumors, tumors of the adrenal medulla, a subcutaneous epithelial tumor in one male, and mammary tumors at an early age in some of the females. Cell-free extracts from a transplanted leukemia and a paraganglioma gave results similar to those obtained with the tissue culture supernatant fluids.

The fine structure of nuclear inclusions in the brain of experimental golden hamsters.

Nuclear bodies and intranuclear fibrillar bundles were observed within the central nervous tissue of the golden hamster after two different experimental procedures. An arbitrary classification of the nuclear bodies into three general types has been proposed. The occurrence of nuclear bodies in a large variety of pathological conditions, and their wide distribution in different types of tissue, renders them of little diagnostic value with respect to the etiology of any particular disease process. The marked increase in the incidence of nuclear bodies, however, in pathological states is indicative of an altered nuclear activity. Their relationship to the fibrillar bundles is unclear. The rarity of fibrillar bundles, even under pathological conditions, leads us to conclude that their presence may be regarded within the normal range of biological variation.

Cytopathogenicity in Tissue Cultures by a Tumor Virus from Mice

Summary Cytopathogenic changes were observed in mouse embryo cell cultures that had been inoculated with tissue culture-grown virus isolated from mouse tumor tissues. Quantitative assays of the virus, referred to as the SE polyoma virus, and serum-virus neutralization tests were correlated with the induction of tumors in hamsters.

Sparing Effect of A-Methopterin and Guanazolo in Mice infected with Virus of Lymphocytic Choriomeningitis.

Abstract An antifolic, a-methopterin, and an antipyrimidine, guanazolo, prolonged or spared the lives of certain mice infected with doses of LCM virus that were uniformly fatal to untreated mice. A-methopterin was more effective than guanazolo, and both were more potent in (C × DBA)F 1 than in Swiss mice under the conditions of these experiments. Infection was not eradicated by the drugs as used, and surviving mice had prolonged periods of viremia. Those tested were found to develop specific immunity.

HERPES-LIKE VIRUS ISOLATED FROM NEONATAL AND FETAL DOGS.

A herpes-like virus has been isolated from fetal and neonatal dogs that died with an acute hemorrhagic disease. The virus differs from the other herpes-like viruses in its immunologic and growth characteristics. It is capable of passing the placental barrier and of causing disease and death of some of the fetuses, but in other apparently healthy animals the virus may remain latent, becoming activated under certain conditions.

The Polyoma Virus Section A

Publisher Summary This chapter gives an overview of polyoma virus. It discusses host response to SE polyoma virus and to tumors and the antigenic properties of SE polyoma virus. Although it has been demonstrated that SE polyoma virus produces tumors in rodents under laboratory conditions, it is known that the parotid gland tumors and others of the spectrum produced in mice rarely are found under natural conditions, even though it has been found that many mouse colonies have the virus as a latent infection. The antigenic response provoked in the host by polyoma virus may account for the absence of spontaneous tumors in infected colonies. It was found that maternal antibodies passed to the nursing off spring in milk inhibit tumor induction. The mechanism by which an oncogenic virus produces tumors is purely speculative at this time, but this is also true of physical and chemical carcinogens. With SE polyoma virus the chapter mentions the progression of events that appear to occur in the development of the mouse tumors.

Folic acid deficiency and the sparing of mice infected with the virus of lymphocytic choriomeningitis

Abstract Mice infected with lymphocytic choriomeningitis (LCM) in normally fatal doses were spared by suitable administration of amethopterin. When citrovorum factor was given along with amethopterin, the sparing effect was essentially eliminated. Mice maintained on diets deficient in folic acid were also spared. It is concluded that folic acid has a critical role in determining the outcome of this type of infection in mice. But virus was recovered from the brains of spared mice in quantities comparable to that in untreated controls. Hence the sparing effect associated with deficiency or blocking of folic acid is not attributable to a need for this metabolite in virus replication. The underlying mechanism that permits mutual survival of host and virus in this situation is still obscure.

Lymphocytic choriomeningitis virus as related to chemotherapy studies and to tumor induction in mice.

In 1956 Stewart and Haas’ recovered and identified LCM virus in 2 sublines of L 1210 leukemia

Influence of Tissue Culture Passage, Storage, Temperature and Drying on Viability of S E polyoma Virus

. One subline designated AMD, FX, reported as A-Methopterin dependent, was obtained from A. Goldin, and the other, subline C, G 153, an ascites tumor carried with 8-azaguanine to the 98th transfer, was obtained from L. W. Laws. Since optimal growth of both sublines occurred in the presence of drugs, the question arose as to whether drug action was in any way conditioned by the presence of the virus. have reported on the sparing effect of A-Methopterin and, to a lesser degree, of 8-azaguanine on mice inoculated with otherwise uniformly lethal doses of LCM. The drugs did not prevent virus survival and replication, but they did prevent death of a large proportion of the mice inoculated with the virus. Humphreys et aZ.6 reported on a contaminant in the same AMD, FX A-Methopterin-dependent subline of leukemia L 1210 referred to above; this agent retarded growth of the tumor if A-Methopterin was withheld. The contaminant was identified as LCM virus.’ The tumor, ordinarily growing optimally in the presence of A-Methopterin, developed equally well in mice immunized against the contaminating agent, even though A-Methopterin was withheld. The “contaminant-free ” leukemia (tumor passed through immune mice) was relatively resistant to A-Methopterin. These reported findings are of interest to experimental chemotherapy of mouse tumors, for mice are known to harbor latent viruses, one of which is LCM. I t is conceivable that a latent virus in tumor cells, or elsewhere in the host, could be activated by the drug under study. The presence of a n active virus in a tumor could make it difficult to interpret the results of chemotherapy studies. Haas and S t e ~ a r t , ~ and Haas et

Zone Electrophoresis Studies on Hemagglutinin of Hemagglutinating and of Masked Strain of Polyoma Virus

Summary The S E polyoma virus derived originally from strain AKR mice can be passed repeatedly from tissue culture to tissue culture. It is relatively stable when stored at −70°C, −20°C or 4°C for 404 to 169 days and it resists the action of ether, glycerol or trypsin. Heating to 80°C destroys or inhibits its tumor inducing property and this property is impaired by heating at 60°C for 60 minutes or 70°C for 30 minutes. It withstands lyo-philization as indicated by induction of multiple tumors in hamsters 1 to 3 days of age with reconstituted lyophilized virus or with the fluids of cultures infected with reconstituted dried virus.