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Novel pegylated interferon-? as strong suppressor of the malignant ascites in a peritoneal metastasis model of human cancer.

ABSTRACT: Malignant ascites manifests as an end-stage event during the progression of a number of cancers and lacks a generally accepted standard therapy. Interferon-? (IFN-?) has been used to treat several cancer indications; however, little is known about the efficacy of IFN-? on malignant ascites. In the present study, we report on the development of a novel, engineered form of human and murine IFN-?, each conjugated with a polyethylene glycol molecule (PEG-hIFN-? and PEG-mIFN-?, respectively). We provide evidence that these IFN-? molecules retain anti-viral potency comparable to unmodified IFN-? in vitro and manifested improved pharmacokinetics in vivo. Interestingly, PEG-mIFN-? significantly inhibited the accumulation of ascites fluid and vascular permeability of the peritoneal membrane in models of ovarian cancer and gastric cancer cell xenograft mice. We further show that PEG-hIFN-? directly suppresses VEGF₁₆₅ -induced hyperpermeability in a monolayer of human vascular endothelial cells and that PEG-mIFN-? enhanced gene expression for a number of cell adhesion related molecules in mouse vascular endothelial cells. Taken together, these findings unveil a hitherto unrecognized potential of IFN-? in maintaining vascular integrity, and provide proof-of-mechanism for a novel and long-acting pegylated hIFN-? for the therapeutic treatment of malignant ascites.

SUBMITTER: Iwamura T

PROVIDER: S-EPMC5406538 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Novel pegylated interferon-β as strong suppressor of the malignant ascites in a peritoneal metastasis model of human cancer.

Iwamura Tomokatsu T Narumi Hideki H Suzuki Tomohiko T Yanai Hideyuki H Mori Katsuyuki K Yamashita Koji K Tsushima Yoshiaki Y Asano Tomomi T Izawa Akiko A Momen Shinobu S Nishimura Kazumi K Tsuchiyama Hiromi H Uchida Masashi M Yamashita Yuji Y Okano Kiyoshi K Taniguchi Tadatsugu T

Cancer science 20170420 4

Malignant ascites manifests as an end-stage event during the progression of a number of cancers and lacks a generally accepted standard therapy. Interferon-β (IFN-β) has been used to treat several cancer indications; however, little is known about the efficacy of IFN-β on malignant ascites. In the present study, we report on the development of a novel, engineered form of human and murine IFN-β, each conjugated with a polyethylene glycol molecule (PEG-hIFN-β and PEG-mIFN-β, respectively). We prov ...[more]

PMID: 28129467

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Project description:ImportanceIndwelling peritoneal catheters (IPCs) are frequently used to drain tense, symptomatic, malignant ascites. Large-volume drainage may lead to hyponatremia owing to massive salt depletion. To date, no studies have examined the epidemiology of hyponatremia after placement of an IPC.ObjectiveTo evaluate the incidence of hyponatremia after IPC placement, the risk factors associated with its development, and how it is managed.Design, setting, and participantsThis cohort study retrospectively reviewed the medical records of 461 patients who had IPCs placed during the period between 2006 and 2016 at a tertiary care hospital in Boston, Massachusetts, of whom 309 patients met the inclusion criteria. Data analysis was performed from June to November 2019.Main outcomes and measuresMain outcomes were the incidence of hyponatremia (with a serum sodium level <135 mEq/L) after IPC placement, the risk factors for its development, and how it was managed. We also examined the clinical course of a subset of 21 patients with hypovolemic hyponatremia.ResultsOf the 309 eligible patients with laboratory results both before IPC placement and 2 days or more after IPC placement, 189 (72.1%) were female, and the mean (SD) age was 59 (12) years. The overall incidence of hyponatremia after IPC placement was 84.8% (n = 262), of whom 21 patients (8.0%) had severe hyponatremia. The mean (SD) decrease in serum sodium level before vs after IPC placement was 5 (5.1) mEq/L and decreased by 10 mEq/L or more among 52 patients (16.8%). Patients with hyponatremia prior to IPC placement had an 8-fold higher adjusted odds of having persistent hyponatremia after IPC placement (odds ratio, 7.9; 95% CI, 2.9-21.7). Patients with hepatopancreatobiliary malignant neoplasms were more likely to develop hyponatremia (78 of 262 patients with hyponatremia [29.8%] vs 7 of 47 patients without hyponatremia [14.9%]). Hyponatremia was either unrecognized or untreated in 189 patients (72.1%).Conclusions and relevanceAlthough the placement of an IPC is often a palliative measure, hyponatremia is common and is often untreated or unrecognized. Patients at highest risk, such as those with hyponatremia at baseline and those with hepatopancreatobiliary malignant neoplams, should be evaluated carefully prior to IPC placement and may warrant closer monitoring after placement. In all cases, hyponatremia should be evaluated and managed within the context of a patient's overall goals of care.

Dataset Information

Novel pegylated interferon-? as strong suppressor of the malignant ascites in a peritoneal metastasis model of human cancer.

Publications

Novel pegylated interferon-β as strong suppressor of the malignant ascites in a peritoneal metastasis model of human cancer.

Similar Datasets

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