Toxicity of Polyinosinic-Polycytidylic Acid Admixed with Poly-&lt;i&gt;L&lt;/i&gt;-Lysine and Solubilized with Carboxymethylcellulose in Mice

Hartmann, D; Schneider, Mark; Lenz, Barbara; Talmadge, James E.

doi:10.1159/000157040

Cited by 18 publications

(10 citation statements)

References 12 publications

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“…The weight results indicate that semiweekly administration of poly ICLC plus bleomycin treatment may produce substantial toxicity, but not in a dose-dependent manner. The synergistic toxicity produced by concomitant administration of bleomycin and poly ICLC in this study is supported by experimental evidence indicating that both bleomycin (Ichikawa et al 1967;Cohen et al 1973) and poly ICLC (Hartmann et al 1987) administered alone may produce organ specific and systemic toxicity. If both bleomycin and poly ICLC did produce toxicity, in some cases affecting the same organ systems, then significant toxicity of a synergistic nature might be the expected result.…”

Section: Discussionsupporting

confidence: 76%

Dose and Regimen Effects of Poly ICLC, an Interferon Inducer, in a Multi‐Dose Bleomycin Model of Interstitial Pulmonary Fibrosis^*

Wild

Hyde

Giri

1994

Pharmacology & Toxicology

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The antifibrotic effects of an interferon inducer, polyinosinic-polycytidylic acid complexed with poly-L-lysine (poly ICLC), was evaluated in a bleomycin-hamster model of pulmonary fibrosis. Hamsters received three consecutive intratracheal doses of bleomycin (2.5, 2.0, and 1.5 U/kg/5 ml) or saline at weekly intervals. Poly ICLC at three doses (0.5, 1.0, and 1.5 mg/kg body weight) or saline was injected intraperitoneally by daily and semiweekly regimens for four weeks, and animals were sacrificed at five weeks. In both the daily and semiweekly poly ICLC regimens, hamsters receiving bleomycin plus poly ICLC demonstrated increased mortality and decreased weight gain compared to the vehicle and bleomycin control groups. The groups receiving bleomycin plus daily poly ICLC demonstrated poly ICLC-dose related effects for weight changes, lung hydroxyproline and lung prolyl hydroxylase activity. Depending on the poly ICLC dose, bleomycin plus daily poly ICLC produced significantly decreased hydroxyproline or significantly increased hydroxyproline and prolyl hydroxylase activity compared to the bleomycin control group. In contrast, the groups receiving bleomycin plus semiweekly poly ICLC did not demonstrate poly ICLC-dose related effects or significant differences from the bleomycin control group for any of the biochemical assays performed. The results of this study indicate that, depending on dose and regimen, poly ICLC can reduce collagen accumulation or produce a synergistic toxicity when administered with multiple doses of bleomycin. The toxic effects may restrict the therapeutic potential of poly ICLC in combination with bleomycin for anticancer therapy.

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Section: Discussionsupporting

confidence: 76%

Dose and Regimen Effects of Poly ICLC, an Interferon Inducer, in a Multi‐Dose Bleomycin Model of Interstitial Pulmonary Fibrosis^*

Wild

Hyde

Giri

1994

Pharmacology & Toxicology

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“…Poly(I:C) has however shown dose-limiting toxicity in animal models as well as in clinical trials, and the reduction of poly(I:C) doses is therefore advised for patient safety. 22,[29][30][31][32] The sequential application of poly(I:C)/R848 may therefore allow better therapeutic efficacy with lower doses of poly(I:C) by sensitizing the TLR7 receptor pathway.…”

Section: Discussionmentioning

confidence: 99%

“…18,22 The simultaneous application of poly(I:C) and R848 was highly toxic at the concentrations used and was thus excluded from in vivo experimentation. Although all sequences tested led to upregulation of the activation marker CD69 on splenic NK1.1 C cells, the highest upregulation was clearly observed following the sequential injection of poly(I:C) and R848 (Fig.…”

Section: Sequential Injections Of Tlr3/mda5 and Tlr7 Ligands Increasementioning

confidence: 99%

Reprogramming of TLR7 signaling enhances antitumor NK and cytotoxic T cell responses

et al. 2016

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Toll-like receptor (TLR) 7 agonists are effective in topical application for the immunotherapy of skin cancers, but their performance for the systemic treatment of solid tumors is limited by the development of TLR tolerance. In this study, we describe a novel strategy to overcome TLR tolerance and enhance TLR7-dependent antitumor immune responses through reprogramming of TLR signaling pathways. The sensitivity of TLR7 signaling in dendritic cells (DC) was increased by prior stimulation with the dsRNA poly (I:C) that mimics virally induced immune activation. Timing of the stimulations was important, as sequential stimulation with poly(I:C) and the TLR7 agonist R848 interspaced by 24 h induced higher MAPK and NFkB signaling in DC than the simultaneous application of the same ligands. DC activated by sequential poly(I:C)/R848 stimulation efficiently induced Th1 differentiation and primed NK-cell and cytotoxic T-cell responses. We have developed a treatment regimen taking advantage of TLR7 reprogramming that cured over 80% of large immunogenic tumors in mice by the action of NK cells and cytotoxic T cells. These results have direct implications for the use of these clinically established ligands in the immunotherapy of cancer.

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“…Other studies have indicated that the maximal tolerated dose of biological response modifiers may not correlate with the optimal immunomodulatory dose or the optimal therapeutic dose [11,43]. In our studies, tumor growth inibition is maximal when mismatched dsRNA is given with rlL-2 at either the 5000-U or the 10000-U dose.…”

Section: Discussionmentioning

confidence: 53%

Antitumor effects of interleukin-2 and mismatched double-stranded RNA, individually and in combination, against a human malignant melanoma xenograft

Hubbell

Vargas

Tsujimoto

et al. 1992

Cancer Immunol Immunother

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The antitumor effects of recombinant interleukin-2 (rIL-2) and mismatched double-stranded RNA (dsRNA) were assessed in tissue culture and in a nude mouse model. Mismatched dsRNA did not show a direct antiproliferative effect against the human malignant melanoma cell line, BRO, in tissue culture. However, treatment of the BRO cells with up to 1000 units/ml rIL-2 in culture showed a slight increase in growth rate. Combined rIL-2/mismatched dsRNA treatment also demonstrated a similar slight enhancement of growth. Nude mice bearing subcutaneous tumors were treated by intraperitoneal injection of low doses (5000-20,000 units) of rIL-2 and mismatched dsRNA (500 micrograms). The in vivo tumor growth was significantly inhibited by the combined treatments (P less than 0.05) and survival was significantly increased (P less than 0.05). Measurement of cytotoxicity using splenocytes from treated animals showed significant augmentation of lytic activity against natural killer (NK)-sensitive YAC-1 cells in all rIL-2/mismatched dsRNA treatment groups, compared to the individual treatments or controls (P less than 0.05). Cytotoxicity of the splenocytes against the NK-resistant BRO cells was also augmented in animals treated with mismatched dsRNA and the highest rIL-2 dose utilized here (P less than 0.01). Renal, liver, and hematological toxicity was evaluated by measurement of blood urea nitrogen, creatinine, serum asparrtate aminotransferase, and a complete blood count with differential. There were no significant differences in these parameters in any of the treatment groups. Similarly, no differences in weight of the animals was seen in any treatment group. These results indicate that the combination of low-dose rIL-2 and mismatched dsRNA can potentiate host-mediated antitumor effects, yielding increased survival, without significant toxicity.

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Toxicity of Polyinosinic-Polycytidylic Acid Admixed with Poly-<i>L</i>-Lysine and Solubilized with Carboxymethylcellulose in Mice

Cited by 18 publications

References 12 publications

Dose and Regimen Effects of Poly ICLC, an Interferon Inducer, in a Multi‐Dose Bleomycin Model of Interstitial Pulmonary Fibrosis^*

Dose and Regimen Effects of Poly ICLC, an Interferon Inducer, in a Multi‐Dose Bleomycin Model of Interstitial Pulmonary Fibrosis^*

Reprogramming of TLR7 signaling enhances antitumor NK and cytotoxic T cell responses

Antitumor effects of interleukin-2 and mismatched double-stranded RNA, individually and in combination, against a human malignant melanoma xenograft

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Toxicity of Polyinosinic-Polycytidylic Acid Admixed with Poly-<i>L</i>-Lysine and Solubilized with Carboxymethylcellulose in Mice

Cited by 18 publications

References 12 publications

Dose and Regimen Effects of Poly ICLC, an Interferon Inducer, in a Multi‐Dose Bleomycin Model of Interstitial Pulmonary Fibrosis*

Dose and Regimen Effects of Poly ICLC, an Interferon Inducer, in a Multi‐Dose Bleomycin Model of Interstitial Pulmonary Fibrosis*

Reprogramming of TLR7 signaling enhances antitumor NK and cytotoxic T cell responses

Antitumor effects of interleukin-2 and mismatched double-stranded RNA, individually and in combination, against a human malignant melanoma xenograft

Contact Info

Product

Resources

About

Dose and Regimen Effects of Poly ICLC, an Interferon Inducer, in a Multi‐Dose Bleomycin Model of Interstitial Pulmonary Fibrosis^*

Dose and Regimen Effects of Poly ICLC, an Interferon Inducer, in a Multi‐Dose Bleomycin Model of Interstitial Pulmonary Fibrosis^*