Treatment of premalignancy: prevention of lymphoma in radiation leukemia virus-inoculated mice by cyclosporin A and immunotoxin.

Yefenof, Eitan; Abboud, Ghada; Epszteyn, Sergio; Vitetta, Ellen S.

doi:10.1073/pnas.89.2.728

Cited by 14 publications

(5 citation statements)

References 22 publications

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“…There There is an interesting parallel between the present studies and our previously employed strategy to prevent development of a murine T-cell lymphoma (44). Thus, radiation leukemia virus-induced premalignant disease is also characdgA and CsA FIG.…”

Section: Discussionsupporting

confidence: 49%

“…The mean p24 level in untreated controls was 60 ng/ml on day 11, 104 ng/ml on day 14, and 94 ng/ml on day 17. terized by cells actively producing virus and a premalignant (latent) population that is subsequently transformed. Replication of the latter is required for the development of a malignant phenotype and requires an IL-4dependent, CsAsensitive autocrine growth loop (44,45). Immunotoxin directed against viral p70 alone or CsA alone (which inhibits IL-4 production) delayed the development of lymphoma but did not prevent the development of lymphoma.…”

Section: Discussionmentioning

confidence: 99%

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Combined use of an immunotoxin and cyclosporine to prevent both activated and quiescent peripheral blood T cells from producing type 1 human immunodeficiency virus.

Bell

Ramilo

Vitetta

1993

Proc. Natl. Acad. Sci. U.S.A.

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Two different populations of infected T cells are present in human immunodeficiency virus (HIV)-infected individuals: activated cells that produce virions and quiescent cells that harbor the viral genome but are unable to produce virus unless they are activated. Using an in vitro model of acute HIV infection, we have evaluated the effect of depleting activated T cells with an immunotoxin and subsequently inhibiting activation of quiescent T cells with an immunosuppressive agent. CD25 (Tac, p55), the alpha chain of the interleukin 2 receptor, is expressed on activated, but not quiescent, T cells. An anti-CD25-ricin A chain immunotoxin eliminated activated, CD25+ HIV-infected cells and, thereby, inhibited viral production by these cells. Subsequent addition of cyclosporine to the residual CD25- cells prevented their activation and thereby suppressed their ability to produce virus and to propagate the infection to uninfected T cells.

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Section: Discussionsupporting

confidence: 49%

Section: Discussionmentioning

confidence: 99%

Combined use of an immunotoxin and cyclosporine to prevent both activated and quiescent peripheral blood T cells from producing type 1 human immunodeficiency virus.

Bell

Ramilo

Vitetta

1993

Proc. Natl. Acad. Sci. U.S.A.

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“…Growth of the cells was inhibited by CyA (17). In addition, a recent report showed that the IIA-dependent growth of RadLV-transformed murine T cells is sensitive to CyA (18). This could indicate that similar, although still uncharacterized, activation-dependent mechanisms are operating in these cells.…”

Section: Discussionmentioning

confidence: 98%

CD2-mediated autocrine growth of herpes virus saimiri-transformed human T lymphocytes.

Mittrücker

Müller-Fleckenstein

Fleckenstein

et al. 1992

The Journal of Experimental Medicine

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SummaryHerpes virus saimiri (HVS) immortalizes T lymphocytes from a variety of primates and causes acute T cell lymphomas and leukemias in nonnatural primate hosts. Here we have analyzed the requirements for growth of three HVS-transformed human T cell lines. The cells expressed the phenotype of activated T cells: two were CD4 + , and one was CD8 + . All three cells responded to all allogeneic human cell lines tested with enhanced proliferation, production of interleukin 2 (Ib2), and increased expression of the I1:2 receptor. Binding of CD2 to its ligand CD58 was the critical event mediating stimulation because: (a) monoclonal antibodies (mAbs) to CD2 and to CD58, but not to a variety of other surface structures, blocked induced and spontaneous proliferation and Ib2 production; (b) only anti-CD2 mAbs were stimulatory if crosslinked; (c) a nonstimulatory cell was rendered stimulatory by CD58 transfection; and (d) the cells responded specifically to CD58 on sheep red blood cells. Growth of the cells required activation because cyclosporin A and FK506 blocked stimulator cell-induced II:2 production and proliferation as well as the spontaneous growth of the lines. Antibodies to the I1:2 receptor reduced proliferation of the cells and blocked 11:2 utilization. Taken together, these results show that HVS-transformed T cells proliferate in response to CD2-mediated contact with stimulator cells or with each other in an I1:2-dependent fashion. They suggest that HVS transforms human T cells to an activationdependent autocrine growth. Herpes virus saimiri (HVS) is the prototype of the lymphotropic 3~-2 herpes viruses (rhadinoviruses). Natural hosts of the virus are the squirrel monkeys (Saimiri sciureus).By cocultivation with permissive monolayer cells, HVS can be isolated from PBL >80% of the population, and at least one in 106 T cells will yield virus (reviewed in reference 1). The virus persists in T cells for their lifetime. HVS is not pathogenic for squirrel monkeys, even after immunosuppression. In contrast to this benign behavior in its natural host, HVS has a high oncogenic potential in numerous other New World primates (1). It causes acute lymphoproliferative syndromes, leukemias, and lymphomas. After infection, the animals die within a few weeks from rapidly progressing neoplasias. Cell lines can be established from infected animals that initially produce virus in "~1-10% of the cells, but after prolonged cultivation the ability to produce virus is lost (2), HVS is able to transform T lymphoeytes of nonhuman primates as well as human PBL and thymocytes to continuous growth (2, 3). The molecular basis of T cell stimulation and transformation is unknown.In this study we show that transformation with HVS induces human T cells to respond to cell-cell contact with each other and with other cells leading to I1:2-dependent autocrine growth. The critical stimulating signal in this contact is given by binding of the CD2 molecule to its natural ligand. These HVS-transformed T cells are the first example of an activation-de...

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“…Although cyclosporine (administered in the diet at a concentration of 0.015% for up to 35 weeks) increased lymphomas in murine leukemia virus + (AKR) mice, 111 it delayed the onset of leukemia in radiation leukemia virus (RadLV)-inoculated C57Bl/6 mice (administered ip at a dose of 50 mg/kg for 2 weeks starting on week 3 after viral inoculation). 112…”

Section: Review Of Preclinical Approaches To Evaluate the Impact Of Immunosuppressive Drugs On Carcinogenesismentioning

confidence: 99%

“…Although cyclosporine (administered in the diet at a concentration of 0.015% for up to 35 weeks) increased lymphomas in murine leukemia virus þ (AKR) mice, 111 it delayed the onset of leukemia in radiation leukemia virus (RadLV)-inoculated C57Bl/6 mice (administered ip at a dose of 50 mg/kg for 2 weeks starting on week 3 after viral inoculation). 112 In summary, testing these drugs gave variable results. Depending on the virus, the immunosuppressive drug, the dose levels administered, and the dosing schedules, increased, decreased, or no effect on tumor incidence was observed.…”

Section: Viral Co-carcinogenesismentioning

confidence: 99%

Critical Review of Preclinical Approaches to Evaluate the Potential of Immunosuppressive Drugs to Influence Human Neoplasia

Bugelski¹,

Volk²,

Walker³

et al. 2010

Int J Toxicol

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Many immunosuppressive drugs are associated with an increased risk of B-cell lymphoma, squamous cell carcinoma, and Kaposi sarcoma. Thirteen immunosuppressive drugs have been tested in 2-year carcinogenicity studies (abatacept; azathioprine; busulfan; cyclophosphamide; cyclosporine; dexamethasone; everolimus; leflunomide; methotrexate; mycophenolate mofetil; prednisone; sirolimus; and tacrolimus) and in additional models including neonatal and genetically modified mice; chemical, viral, ultraviolet, and ionizing radiation co-carcinogenesis, and in models with transplanted tumor cells. The purpose of this review is to outline the mechanisms by which immunosuppressive drugs can influence neoplasia, to summarize the available preclinical data on the 13 drugs, and to critically review the performance of the models. A combination of primary tumor and metastasis assays conducted with transplanted cells may provide the highest value for hazard identification and can be applied on a case-by-case basis. However, for both small molecules and therapeutic proteins, determining the relative risk to patients from preclinical data remains problematic. Classifying immunosuppressive drugs based on their mechanism of action and hazard identification from preclinical studies and a prospective pharmacovigilance program to monitor carcinogenic risk may be a feasible way to manage patient safety during the clinical development program and postmarketing.

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Treatment of premalignancy: prevention of lymphoma in radiation leukemia virus-inoculated mice by cyclosporin A and immunotoxin.

Cited by 14 publications

References 22 publications

Combined use of an immunotoxin and cyclosporine to prevent both activated and quiescent peripheral blood T cells from producing type 1 human immunodeficiency virus.

Combined use of an immunotoxin and cyclosporine to prevent both activated and quiescent peripheral blood T cells from producing type 1 human immunodeficiency virus.

CD2-mediated autocrine growth of herpes virus saimiri-transformed human T lymphocytes.

Critical Review of Preclinical Approaches to Evaluate the Potential of Immunosuppressive Drugs to Influence Human Neoplasia

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