Plasma protein (albumin) catabolism by the tumor itself—implications for tumor metabolism and the genesis of cachexia

Stehle, Gerd; Sinn, H.; Wunder, Andreas; Schrenk, H. H.; Stewart, James; Hartung, G.; Maier‐Borst, W.; Heene, D. L.

doi:10.1016/s1040-8428(97)00015-2

Cited by 281 publications

(196 citation statements)

References 172 publications

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“…More importantly, the IC 50 values on tumor cell viability for clioquinol are not dissimilar from the trough blood concentrations documented in a recent clinical trial of clioquinol in patients with Alzheimer's disease (18). The apparent tolerability of normal tissues for clioquinol in the face of tumor growth inhibition seen in xenograft-bearing animals may relate to the fact that clioquinol binds albumin with high affinity (37) and albumin selectively targets tumors (38).…”

Section: Discussionmentioning

confidence: 76%

Anticancer Activity of the Antibiotic Clioquinol

et al. 2005

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Clioquinol, a metal chelator, has been used for many years as an antimicrobial agent and more recently as a potential treatment for Alzheimer's disease. Because it binds copper and zinc, metals essential for the activity of the enzyme superoxide dismutase-1 (SOD1), a potential target for anticancer drug development, we investigated its effects on human cancer cells. Treatment with clioquinol reduced the viability of eight different human cancer cell lines in a concentration-dependent manner, with IC 50 values in the low micromolar range. Biochemical analysis revealed that clioquinol induced cancer cell death through apoptotic pathways that require caspase activity. Although clioquinol induced modest inhibition of SOD1 activity in treated cells, comparable inhibition by a known SOD1 inhibitor, diethyldithiocarbamate, did not result in cytotoxicity. The addition of copper, iron, or zinc did not rescue cells from cliquinol-induced cytotoxicity but enhanced its killing, arguing against metal chelation as its major mechanism of action. To test if clioquinol might act as an ionophore, a fluorescent probe was used to monitor intracellular zinc concentrations. The addition of clioquinol resulted in elevated levels of intracellular zinc, indicating that clioquinol acts as a zinc ionophore. In an in vivo xenografts mouse model, clioquinol inhibited tumor growth of xenografts over a 6-week period, without inducing visible toxicity. Our results show that clioquinol has anticancer effects both in vitro and in vivo. Transition metal ionophores may be a subclass of metal chelators with anticancer activity deserving of further development. (Cancer Res 2005; 65(8): 3389-95)

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Section: Discussionmentioning

confidence: 76%

Anticancer Activity of the Antibiotic Clioquinol

et al. 2005

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“…Known to accumulate in and be catabolized by tumors, albumin has previously been pursued as a delivery vehicle for chemotherapy (14)(15)(16)(17)(18). Combining this observation with immunotherapy, we explore the ability of an albumin-binding Fab (AB.Fab) to specifically target tumors.…”

Section: Introductionmentioning

confidence: 99%

Imaging Tumors with an Albumin-Binding Fab, a Novel Tumor-Targeting Agent

Dennis¹,

et al. 2007

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Association with albumin as a means to improve biodistribution and tumor deposition of a Fab was investigated using AB.Fab4D5, a bifunctional molecule derived from trastuzumab (HERCEPTIN) capable of binding albumin and tumor antigen HER2 (erbB2) simultaneously. AB.Fab4D5 was compared with trastuzumab and a trastuzumab-derived Fab (Fab4D5) for the ability to target tumors overexpressing HER2 in mouse mammary tumor virus/HER2 allograft models. Biodistribution was monitored using intravital microscopy, histology, and integrated single-photon emission computed tomography/ computed tomography analysis. Fab4D5 tumor deposition was characterized by rapid but transient appearance in tumor at 2 h with little retention, followed by rapid accumulation in kidney by 6 h. Trastuzumab was slow to accumulate in tumors and slow to clear from normal tissues, although significant tumor deposition was achieved by 24 h. In contrast, AB.Fab4D5 was observed at 2 h in tumor and its presence was sustained beyond 24 h similar to trastuzumab. Intravital microscopy revealed that at peak tumor accumulation, tumor cell staining by AB.Fab4D5 was more uniform than for Fab4D5 or trastuzumab. Similar tumor deposition was achieved for both AB.Fab4D5 and trastuzumab at 48 h (35.9 F 1.8% and 38.2 F 3.1% injected dose/g); however, AB.Fab4D5 targeted tumors more rapidly and quickly cleared from blood, leading to a lower overall normal tissue exposure. Importantly, unlike Fab4D5, AB.Fab4D5 did not accumulate in kidney, suggesting that association with albumin leads to an altered route of clearance and metabolism. Rapid targeting, excellent tumor deposition and retention, coupled with high tumor to blood ratios may make AB.Fab an exceptional molecule for imaging and cancer therapy. [Cancer Res 2007;67(1):254-61]

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“…We observed that serum albumin levels overall were significantly lower in stage 4 versus stages 1-3 (p ≤ 0.05; Table 2). Albumin is a negative acute phase protein and its serum levels in cancer may decrease due to decreased synthesis, increased catabolism and other mechanisms [25][26][27][28][29]. In our study, a multivariate regression analysis adjusting for age, gender and MM site, every 1.0 mg/dl increase in albumin-corrected future science group www.futuremedicine.com serum calcium increased the odds of higher MM stage by 60%.…”

Section: Discussionmentioning

confidence: 50%

Serum Calcium, Albumin and Tumor Stage in Cutaneous Malignant Melanoma

et al. 2016

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High albumin adjusted serum calcium has been reported in several cancers but has not been studied in malignant melanoma. We examined the relationship between serum albumin, total and corrected calcium in malignant melanoma in a cross‐sectional study. Two thousand three hundred six patients with cutaneous melanoma were identified between Jan. 2000 and Dec. 2010 and 644 met our inclusion criteria. At the time of diagnosis, total serum calcium was non‐significantly lower in stage 4 (9.34 mg/dL) vs. stages 1‐3 (9.48‐9.51 mg/dL). Serum albumin was significantly lower in stage 4 (3.92 g/dL; p蠄0.05) than stages 0‐3 (4.09‐4.15 g/dL). Higher albumin corrected serum calcium was observed with increasing melanoma stage (9.45‐9.61 mg/dL). Men but not women showed a significant decrease in serum albumin in stage 4 when compared with stages 1‐3 (p = 0.02). Patients >75 years had significantly lower serum albumin (3.98±0.33 vs 4.16±0.35 g/dL; p<0.001), but higher adjusted calcium (9.64±0.49 vs 9.53±0.43 mg/dL; p=0.03) compared to patients 蠄 75 years. Serum albumin may serve as a biomarker to evaluate disease progression in cutaneous malignant melanoma patients. Grant Funding Source: Dr. Datta is supported by the Comprehensive Cancer Center of Wake Forest University Cancer Control Traineeship ‐ NCI/NIH Grant# #R25CA122061.

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Plasma protein (albumin) catabolism by the tumor itself—implications for tumor metabolism and the genesis of cachexia

Cited by 281 publications

References 172 publications

Anticancer Activity of the Antibiotic Clioquinol

Anticancer Activity of the Antibiotic Clioquinol

Imaging Tumors with an Albumin-Binding Fab, a Novel Tumor-Targeting Agent

Serum Calcium, Albumin and Tumor Stage in Cutaneous Malignant Melanoma

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