Abstract 2821: Dual-label microdosing approach to identify chemoresistance to carboplatin and gemcitabine combination chemotherapy
Maike Zimmermann, Tiffany M. Scharadin, Hongyong Zhang, Tzu-Yin Lin, Ralph W. deVere White, Chong-Xian Pan, Paul T. Henderson
Cancer Research October 1, 2014 DOI: 10.1158/1538-7445.am2014-2821 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study (conference abstract) Peer reviewed |
|---|---|
| Population | Bladder cancer cell lines and NSG mice bearing patient-derived tumor xenografts from bladder cancer patients |
| Interventions | Gemcitabine Carboplatin [14C]carboplatin microdose |
| Dose | microdose of gemcitabine (single non-toxic microdose); carboplatin microdose at 1% of therapeutic dose |
| Measures | accelerator mass spectrometry (AMS) |
| Topics | Microdosing |
| Key points | The authors propose that drug-DNA adduct levels formed after a single microdose of gemcitabine plus carboplatin, measured by accelerator mass spectrometry, are proportional to those formed during full-dose chemotherapy, and they hypothesize a threshold adduct level above which tumors respond to GC therapy. They report progress on developing protocols and preliminary microdosing data in the NSG-PDX mouse model; no results are given. |
Abstract
Abstract: Gemcitabine is commonly given in combination with cisplatin or carboplatin (GC therapy) as the first-line chemotherapy regimen for several malignancies, including bladder cancer. Unfortunately, less than half of patients respond to the therapy, generating a critical need for a test that predicts tumor response to GC therapy. The goal of this project is to measure drug-DNA adducts after administration of a single non-toxic microdose of gemcitabine in combination with carboplatin and correlating the degree of modification to chemotherapy sensitivity. We have previously shown that resistance to carboplatin may be identified by using a [14C]carboplatin microdose (1% of therapeutic dose), and subsequent measurement of the [14C]-DNA adducts via accelerator mass spectrometry (AMS), an ultrasensitive method used for detecting rare isotopes. We postulate that adduct levels induced in tumors by GC microdoses are proportional to those formed during full dose chemotherapy. Furthermore, we hypothesize that there exists a threshold level of adducts above which tumors respond to GC therapy. We used bladder cancer cell lines and the nod scid gamma severe combined immunodeficient (NSG) mice containing patient-derived tumor xenografts (PDX) from bladder cancer patients to determine GC-DNA adduct levels using AMS. The NSG mouse is uniquely capable of accepting and propagating tumor tissue engrafted directly from patient biopsy samples. The resulting groups of mice each have identical tumors, but can be treated in a variety of ways with replicate experiments; characteristics that are impossible to achieve in normal clinical studies. We will report progress on developing protocols and preliminary GC microdosing data using the NSG-PDX mouse model of human bladder cancer. Citation Format: Maike Zimmermann, Tiffany M. Scharadin, Hongyong Zhang, Tzu-yin Lin, Ralph W. deVere White, Chong-xian Pan, Paul T. Henderson. Dual-label microdosing approach to identify chemoresistance to carboplatin and gemcitabine combination chemotherapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2821. doi:10.1158/1538-7445.AM2014-2821
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 | |
| Toward Predicting Acute Myeloid Leukemia Patient Response to 7 + 3 Induction Chemotherapy via Diagnostic Microdosing Paired sensitive and resistant cancer cell lines, AML cell lines, and 10 viably... | 2018 | Preclinical cell line study with a pilot retrospective analysis of primary patient samples | n = 10 |