Viruses as an Aid to Cancer Therapy: Regression of Solid and Ascites Tumors in Rodents After Treatment with Bovine Enterovirus

Abstract

Treatment of ascites and solid tumors in mice (Sarcoma-I and Ehrlich ascites carcinoma) with bovine enterovirus-I resulted in regression of the tumors without any pathological effect on the animals. Death of mice with lymphatic-leukemia L4946 was delayed after such treatment. The oncolytic specificity of the virus does not appear to involve the production of interferon, but requires specific adsorption of virus to the tumor cells. The specificity of killing extends to cells in culture, since viral-transformed cells and oncogenic cells are susceptible to the virus, in contrast to cells of untransformed lines and cells of primary cultures, which are resistant.The possibility of utilizing the specificity of nonvirulent viruses in therapeutic treatment of human cancers is considered.The use of viruses specific for the destruction of cancer has remained essentially a laboratory curiosity. Many researchers have suggested that it should be possible to utilize biological mechanisms with sufficient specificity to discriminate between a malignant tumor cell and a normal cell in order to control tumor growth. During the last forty years, a few laboratories have investigated this possibility with different viruses (1-3). However, apart from a report (4) of the partial inhibition of a transplantable murine leukemia by M-P virus, most oncolytic viruses have been found to be too lethal for the host for this treatment to be practical.A few successful instances of oncolysis in man have been reported. However, the results of such experiments are difficult to evaluate since viral treatment followed other therapeutic measures that could have played a part in tumor regression. Wheelock and Dingle (5) achieved a temporary remission of acute leukemia in a human subject by successive inoculation of six different viruses.In this paper, we present evidence of viral oncolysis in rodents carrying both solid and ascites tumors without any apparent effect on the host animal. MATERIALS AND METHODS Virus productionBovine enterovirus-1 (BEV-1) was grown in cell monolayers of Maden Bovine kidney or mouse L-cells in Eagle's minimal essential medium supplemented with 5% chick serum, streptomycin (100 Mg/ml), penicillin (100 units/ml), and fungizone (2.5 ,zg/ml). High-titer lysates of BEV-1 were produced by infecting monolayers of confluent roller cultures (690 cm2; about 5 X 108 cells) with virus at a multiplicity of infection of 1-10 plaque-forming units (PFU)/cell in medium without serum. Cultures were rolled for 1 hr at 1 rpm on a Bellco roller apparatus to allow virus adsorption. At that time, fresh medium containing 5% serum was added, and infected cells were incubated 12-15 hr. Bottles were passed through three cycles of freeze and thaw to release virus. The cell debris was removed by centrifugation for 10 min at 3000 rpm. Lysates were stored in small aliquots at -20°C. BEV-1 was assayed by the plaque technique and hemagglutination as previously described (6). TumorsEhrlich ascites tumor and Sarcoma-1 (SA-1), in ascites form, were ma...

Effect of Double-Stranded Viral RNA on Mammalian Cells in Culture

“…We have previously reported that BEV is a relatively efficient oncolytic agent (19). We feel this efficiency is due to the propensity of this virus to produce large amounts of double-stranded RNA.…”

Bovine enterovirus as an oncolytic virus: Foetal calf serum facilitates its infection of human cells

“…While much work remains to be carried out on BEV's oncolytic properties, clearly the results shown here together with previous discontinued studies (15,17) indicate the virus to be worthy of inclusion with those viruses being investigated for cancer therapy.…”

“…Furthermore it has been shown that treatment with BEV could cause regression of solid and ascites tumours in rodents (17).…”

Oncolysis of human ovarian cancers by echovirus type 1

“…9 In addition to CVA21, other enteroviruses reported to exhibit oncolytic potential in human cancer cells are a genetically modified strain of poliovirus 1 10 and a nonaltered strain of bovine enterovirus. 11,12 Enteroviral infection of many in vitro cell cultures is characterized by rapid induction of gross cytolytic changes in cell morphology, with the underlining determinant of the cellular tropism being the relative surface expression of specific virus receptors enabling virus attachment and cell entry. One enteroviral cellular receptor molecule widely expressed on ovarian cancer cells at high levels on the cell surface is integrin a 2 b 1 .…”