Toward Predicting Acute Myeloid Leukemia Patient Response to 7 + 3 Induction Chemotherapy via Diagnostic Microdosing
Tiffany M. Scharadin, Michael Malfatti, Kurt W. Haack, Kenneth Wayne Turteltaub, Chong-Xian Pan, Paul T. Henderson, Brian Andrew Jonas
Chemical Research in Toxicology August 28, 2018 DOI: 10.1021/acs.chemrestox.8b00107 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical cell line study with a pilot retrospective analysis of primary patient samples Peer reviewed |
|---|---|
| Sample size | 10 |
| Population | Paired sensitive and resistant cancer cell lines, AML cell lines, and 10 viably cryopreserved primary AML samples |
| Interventions | Cytarabine (ARA-C) Idarubicin (IDA) |
| Measures | IC50 values, drug-DNA adduct levels |
| Topics | Microdosing |
| Citations | 4 |
| Key points | The authors report proof of principle that cytarabine- and doxorubicin-DNA adduct levels correlate with cellular IC50 values in paired sensitive and resistant cancer cell lines, and in a pilot retrospective trial of 10 primary AML samples, higher cytarabine- and doxorubicin-DNA adducts occurred in 7 + 3 responders than nonresponders. They suggest diagnostic microdosing may be a feasible test for predicting response to 7 + 3 induction chemotherapy. |
Abstract
Acute myeloid leukemia (AML) is a rare yet deadly cancer of the blood and bone marrow. Presently, induction chemotherapy with the DNA damaging drugs cytarabine (ARA-C) and idarubicin (IDA), known as 7 + 3, is the standard of care for most AML patients. However, 7 + 3 is a relatively ineffective therapy, particularly in older patients, and has serious therapy-related toxicities. Therefore, a diagnostic test to predict which patients will respond to 7 + 3 is a critical unmet medical need. We hypothesize that a threshold level of therapy-induced 7 + 3 drug-DNA adducts determines cytotoxicity and clinical response. We further hypothesize that in vitro exposure of AML cells to nontoxic diagnostic microdoses enables prediction of the ability of AML cells to achieve that threshold during treatment. Our test involves dosing cells with very low levels of 14 C-labeled drug followed by DNA isolation and quantification of drug-DNA adducts via accelerator mass spectrometry. Here, we have shown proof of principle by correlating ARA-C- and DOX-DNA adduct levels with cellular IC 50 values of paired sensitive and resistant cancer cell lines and AML cell lines. Moreover, we have completed a pilot retrospective trial of diagnostic microdosing for 10 viably cryopreserved primary AML samples and observed higher ARA-C- and DOX-DNA adducts in the 7 + 3 responders than nonresponders. These initial results suggest that diagnostic microdosing may be a feasible and useful test for predicting patient response to 7 + 3 induction chemotherapy, leading to improved outcomes for AML patients and reduced treatment-related morbidity and mortality.
Comparable studies
Other preclinical and animal studies on microdosing, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocin and ketamine microdosing: effects of subchronic intermittent microdoses in the elevated plus-maze in male Wistar rats Wistar rats | 2018 | Experimental study | n = 40 |
| Repeated low doses of psilocybin increase resilience to stress, lower compulsive actions, and strengthen cortical connections to the paraventricular thalamic nucleus in rats. Rats | 2023 | Experimental study | |
| Repeated microdoses of LSD do not alter anxiety or boldness in zebrafish. Zebrafish (Danio rerio) | 2024 | Experimental study | |
| Application of microarray patches for the transdermal administration of psychedelic drugs in micro-doses. Excised neonatal porcine skin and rats | 2025 | Experimental study | |
| Assessing the Potential Cardiovascular Risk of Microdosing the Psychedelic LSD in Mice Mice | 2025 | Animal study |