Interleukin-2 toxicity.

Siegel, Jay P.; Puri, Roj K.

doi:10.1200/jco.1991.9.4.694

Cited by 419 publications

(192 citation statements)

References 66 publications

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“…1,2 While repeated exposure to low doses of cytokines in the tumor site have resulted in a strong antitumor immune response, 3,4 the usual limitation is toxicity. [5][6][7] Transfected cells secreting cytokines such as GM-CSF, IL-2, IL-4, IFN␥ or IL-12 have been used as vaccines to induce antitumor responses in mice. [8][9][10][11][12] However, toxicity of transduced cells and of the released cytokines, [13][14][15] bystander T cell activation or expansion and differentiation of T cells without apparent specificity for the tumor antigen has been observed.…”

Section: Introductionmentioning

confidence: 99%

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Tumor cells expressing membrane-bound form of IL-4 induce antitumor immunity

Kim

Sonn

et al. 2000

Gene Ther

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Local cytokine concentrations are required for inhibition of tumor growth with less toxic side-effects. However, genetically engineered tumor cells secreting cytokines still induce toxicity and activate bystander cells. To circumvent such problems, membrane-bound forms of IL-4 (IL-4m) were expressed on MethA fibrosarcoma tumor cells. Chimeric forms of IL-4 with the type I transmembrane protein CD4 or type II transmembrane protein TNF were designed to express IL-4 in opposite orientations on the tumor cell surface. The IL-4m on tumor clones was able to support cell growth of the IL-4 dependent cytotoxic cell line (CT.4S) and

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Section: Introductionmentioning

confidence: 99%

“…This strategy should also alleviate problems of toxicity encountered with soluble cytokines. [5][6][7][13][14][15] …”

Section: Introductionmentioning

confidence: 99%

Tumor cells expressing membrane-bound form of IL-4 induce antitumor immunity

Kim

Sonn

et al. 2000

Gene Ther

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“…Capillary leak syndrome is a major side-effect of high-dose IL-2 therapy, characterised by retention of extravascular fluid and hypotension (Siegel and Puri, 1991). It has been observed in humans (Siegel and Puri, 1991; Margolin et al, 1989;Rosenberg et al, 1987) al., 1985) and tumour necrosis factor (TNF)-ca (Kahaleh et al, 1988); and finally, vasodilation due to IL-2-induced production of nitric oxide (NO) Ochoa et al, 1992), leading to systemic hypotension followed by pulmonary hypertension and oedema.There have been several reports of therapies that combine IL-2 with agents that might ameliorate the capillary leakage. However, the added drugs also opposed the anti-tumour effects of IL-2.…”

mentioning

confidence: 99%

“…Widespread clinical use of IL-2 has been limited by the low rate of complete remission and by severe toxicity Siegel and Puri, 1991). Capillary leak syndrome is a major side-effect of high-dose IL-2 therapy, characterised by retention of extravascular fluid and hypotension (Siegel and Puri, 1991).…”

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NG-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthesis, ameliorates interleukin 2-induced capillary leakage and reduces tumour growth in adenocarcinoma-bearing mice

Orucevic

Lala

1996

Br J Cancer

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Summary We tested whether NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) synthesis, can prevent interleukin 2 (IL-2)-induced capillary leakage in tumour-bearing mice without compromising the therapeutic benefits of IL-2. C3H/HeJ female mice transplanted s.c. with 2.5 x 105 C3-L5 mammary carcinoma cells were treated with: nothing, IL-2 (ten injections of 15 000 Cetus units i.p. every 8 h), L-NAME (0.1, 0.5, or 1 mg ml-1 drinking water), IL-2+L-NAME (0.1 or 0.5 or 1 mg ml-' drinking water).Therapies were given in one round (IL-2, days 10-13; L-NAME, days 9-13) or in two rounds (IL-2, days 10-13 and 20-23; L-NAME, days 9-13 and days 19-23) after tumour transplantation. Capillary leakage was measured from the water contents of the pleural cavities, lungs, spleen and kidneys. Effects of the therapies on the primary tumour size and the number of spontaneous lung metastases were also recorded. NO production was measured as the nitrite+nitrate levels in the serum and in the pleural effusion. After the first round of therapies, addition of L-NAME significantly reduced IL-2-induced pulmonary oedema and water retention in the spleen in a dose-dependent manner. It also significantly reduced the IL-2-induced rise in NO levels in the serum and pleural fluid, but did not affect IL-2-induced pleural effusion or water retention in the kidney. At later stages of tumour growth (day 23), tumours themselves induced significant fluid retention in the lungs and the kidney, which was not aggravated further with the second round of IL-2 therapy. At this time, L-NAME therapy alone ameliorated tumour-induced pulmonary oedema. During both rounds of therapy different doses of L-NAME alone caused a reduction of primary tumour growth as well as spontaneous lung metastases, which improved further with the addition of IL-2. The combination therapy was at least as effective as IL-2 therapy. In summary, L-NAME had anti-tumour effects in vivo, reduced the severity of IL-2-induced capillary leakage in some organs and did not compromise anti-tumour efficacy of IL-2 therapy. Thus, L-NAME could be a valuable adjunct to IL-2-based cancer therapy.Keywords: capillary leak syndrome; interleukin 2 cancer immunotherapy; mammary adenocarcinoma; nitric oxide; NG-nitro-L-arginine methyl ester Interleukin 2 (IL-2) therapy, alone or in combination with ex vivo-generated lymphokine-activated killer (LAK) cells, can cause tumour regression in mice (Rosenberg et al., 1985;Ettinghausen et al., 1988) and in man (Rosenberg, 1989;Fisher et al., 1988; Dutcher et al., 1989;Parkinson et al., 1990). Widespread clinical use of IL-2 has been limited by the low rate of complete remission and by severe toxicity Siegel and Puri, 1991). Capillary leak syndrome is a major side-effect of high-dose IL-2 therapy, characterised by retention of extravascular fluid and hypotension (Siegel and Puri, 1991). It has been observed in humans (Siegel and Puri, 1991; Margolin et al., 1989;Rosenberg et al., 1987) al., 1985) and tumour necrosis factor (TNF)-ca...

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Low Infection Rate and Long Durability of Nontunneled Silastic Catheters

Raad¹

1993

Arch Intern Med

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Interleukin-2 toxicity.

Cited by 419 publications

References 66 publications

Tumor cells expressing membrane-bound form of IL-4 induce antitumor immunity

Tumor cells expressing membrane-bound form of IL-4 induce antitumor immunity

NG-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthesis, ameliorates interleukin 2-induced capillary leakage and reduces tumour growth in adenocarcinoma-bearing mice

Low Infection Rate and Long Durability of Nontunneled Silastic Catheters

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