Phase IIa Clinical Biomarker Trial of Dietary Arginine Restriction and Aspirin in Colorectal Cancer Patients - PubMed (original) (raw)

Phase IIa Clinical Biomarker Trial of Dietary Arginine Restriction and Aspirin in Colorectal Cancer Patients

Jason A Zell et al. Cancers (Basel). 2023.

Abstract

After potentially curative treatment, colorectal cancer (CRC) patients remain at high risk for recurrence, second primary CRC, and high-risk adenomas. In combination with existing data, our previous findings provide a rationale for reducing tissue polyamines as tertiary prevention in non-metastatic CRC patients. The goal of this study was to demonstrate rectal tissue polyamine reduction in optimally treated stage I-III CRC patients after intervention with daily oral aspirin + dietary arginine restriction. A single-institution phase IIa clinical trial was conducted. Patients were treated with aspirin 325 mg/day and an individualized dietary regimen designed to reduce arginine intake by ≥30% over a 12-week study period. Dietary intake, endoscopy with rectal biopsies, and phlebotomy were performed pre- and post-intervention. The primary endpoint was to demonstrate ≥50% decrease in rectal tissue putrescine levels from baseline as a measure of polyamine reduction in the target tissue. Twenty eligible patients completed the study. After study intervention, mean dietary arginine intake decreased from 3.7 g/day ± 1.3 SD to 2.6 g/day ± 1.2 SD (29.7% decrease, p < 0.02 by Sign test). Mean plasma arginine levels decreased from 46.0 ng/mL ± 31.5 SD at baseline to 35 ng/mL ± 21.7 SD (p < 0.001). Rectal tissue putrescine levels were 0.90 nMol/mg-protein pre-intervention and 0.99 nMol/mg-protein post-intervention (p < 0.64, NS). No significant differences were observed for the other tissue polyamines investigated: spermidine (p < 0.13), spermine (p < 0.21), spermidine:spermine ratio (p < 0.71). Among CRC survivors, treatment with daily oral aspirin and an individualized dietary arginine restriction intervention resulted in lower calculated dietary arginine intake and plasma arginine levels but did not affect rectal tissue polyamine levels.

Keywords: arginine restriction; aspirin; cancer prevention; clinical trial; colorectal cancer; dietary intervention; polyamines.

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Conflict of interest statement

The authors list the following disclosures: J.Z.: Tempus; C.A.: Nestle Health Sciences, AbbVie, Phathom Pharmaceuticals, DSI Pharmaceuticals, Salix Pharmaceuticals; J.C.: Johnson & Johnson; L.W.: Immunogen.

Figures

Figure 1

Figure 1

Arginine as the central substrate for polyamine and nitric oxide metabolism. Alternate pathways and inhibitors are indicated. NOS, nitric oxide synthase; DFMO, difluoromethylornithine (eflornithine); ODC, ornithine decarboxylase; NSAIDs, non-steroidal anti-inflammatory drugs; SSAT, spermidine/spermine _N_1-acetyltransferase; OAT, ornithine aminotransferase.

Figure 2

Figure 2

Clinical procedures involved in the Phase IIa Clinical Trial.

Figure 3

Figure 3

Dietary Arginine Intake, post- vs. pre-intervention (dietary arginine restriction and oral aspirin 325 mg daily). Measurements missing for n = 3 patients.

Figure 4

Figure 4

Rectal Tissue Putrescine Levels, post- vs. pre-intervention (dietary arginine restriction and oral aspirin 325 mg daily).

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