The long-term objective of this research is to develop a non-invasive approach for early assessment of de novo 3MH production in cancer patients as a way of assessing which patients are at high risk for future development of skeletal muscle atrophy. The approach is based on the known increase in the rate constant for de novo production of 3-methylhistidine (3MH) in this sub-set of cancer patients as a consequence of their unique tumor-host interactions. As such, we hypothesize that the rate constant for the terminal portion of the isotope decay curve following ingestion of a single oral dose of deuterated-3-methylhistidine (D-3MH) provides an accurate measure of this increased risk and that this rate constant can be measured non-invasively from timed spot urine samples obtained during this period. Furthermore, we hypothesize that consumption of 3MH- containing meals up to the time of dosing will not adversely affect the results making the entire procedure clinically relevant. During Phase I, we will establish the feasibility of our over all approach by testing the following hypotheses: (i) isotope enrichment in spot urine samples is identical with the corresponding plasma samples, and (ii) meat intake up to and including the time of dosing does not influence the slope of the terminal portion of the isotope decay curve. Testing the validity of these two hypotheses is the central focus of the Phase-I research and is crucial to the development of an approach that is both scientifically sound as well as non-invasive and clinically relevant. We will test the feasibility of our approach in ten healthy older adult male volunteers. If Phase-I testing is successful, we propose, with Phase-II funding, to conduct a statistically powerful prospective investigation to demonstrate that this test conducted in newly diagnosed lung and gastrointestinal cancer patients predicts future development of muscle wasting. We expect the outcome of the combined Phase-I and Phase-II research to lead to the manufacture and marketing of a suitable """"""""Test Kit"""""""" for early identification of increased muscle proteolysis in at-risk cancer patients so that medical intervention can take place and prevent future muscle atrophy. ? ? Project Narrative: Skeletal muscle loss is an important, but unpredictable, occurrence in patients with different types of cancer. Clinically significant skeletal muscle loss cannot be reversed and has poor prognostic implications. Its early assessment is important because it would permit selection of cancer patients for preventive strategies. The purpose of this project is to develop a non-invasive method for early assessment of increased skeletal muscle degradation in patients with cancer. Our approach is based on development of a (non-radioactive) stable isotope tracer approach to permit accurate quantitative measurement of skeletal muscle degradation early in the course of muscle loss by monitoring spot urine samples for the ratio of labeled/unlabeled 3-methylhistidine the morning after consuming a small amount of labeled 3-methylhistidine along with dinner. ? ? ?
| Sheffield-Moore, M; Dillon, E L; Randolph, K M et al. (2014) Isotopic decay of urinary or plasma 3-methylhistidine as a potential biomarker of pathologic skeletal muscle loss. J Cachexia Sarcopenia Muscle 5:19-25 |
