RT Journal Article
SR Electronic
T1 <strong><sup>99m</sup></strong><strong>Tc-duramycin imaging reveals variable tissue toxicity of cancer drugs</strong>
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 1286
OP 1286
VO 59
IS supplement 1
A1 Deborah Sneddon
A1 Julia Baguña Torres
A1 Sophie Badie
A1 Madalena Tarsounas
A1 Bart Cornelissen
YR 2018
UL http://jnm.snmjournals.org/content/59/supplement_1/1286.abstract
AB 1286Objectives: Cisplatin and chlorambucil are alkylating antineoplastic chemotherapy agents, widely used for the treatment of solid tumours and chronic lymphocytic leukaemia (CLL) respectively. 1,2 Cisplatin induces cell death by apoptosis and has been shown to have several toxic side effects including nephrotoxicity, cardiotoxicity and hepatotoxicity.3 Chlorambucil also induces apoptosis and its administration is associated with reversible bone marrow suppression2 but its excretion seems to be independent from kidney function.2 Chlorambucil has shown reduced toxicity when compared to purine nucleoside analogues4 and therefore, we were interested in comparing the toxicity effects of cisplatin and chlorambucil. To this end, we undertook an investigation to compare the toxicity effects of both drugs in vivo by SPECT imaging using 99mTc-Duramycin, which recognises apoptotic and necrotic cells by binding to phosphatidyethanolamine. Methods: Wildtype BALB/c mice were injected with 3 mg/kg/day with either chlorambucil (n=5), cisplatin (n=5) or saline (sham group, n=4) for 5 days. 99mTc-Duramycin was prepared as previously described by Wyffels and coworkers.5 The purity was checked by RP18 HPLC and confirmed to be over 95%. Mice (day 0 and 7) were injected intravenously with 1 µg of 99mTc-Duramycin (2-6 MBq) and imaged after 2 hours using a MILabs VECTor® PET/SPECT/CT scanner. After the final imaging session, organs of interest were excised and gamma-counted for ex vivo biodistribution analysis. Results: Ex vivo tissue counting (Figure 1) revealed a significant (P&lt;0.001, one-way ANOVA (Bonferroni multiple comparison test)) increase in 99mTc-Duramycin accumulation in the small intestine (8.89±1.12 %ID/g) and lungs (6.36±1.01 %ID/g) of the cisplatin-treated mice compared to the sham control group (1.97±0.28 and 1.36±0.1 %ID/g respectively) and their chlorambucil-treated counterparts (1.85±0.22 and 1.35±0.12 %ID/g respectively) (Figure 1). The nephrotoxicity of cisplatin is widely reported3, and as expected, there is a significantly higher accumulation of 99mTc-Duramycin in the kidneys for the cisplatin-treated group compared to the sham group (P&lt;0.01, 63.57±6.96 and 37.15±3.44 %ID/g respectively) and to the chlorambucil-treated group (P&lt;0.05, 43.41±2.38 %ID/g). The higher blood concentration of 99mTc-Duramycin in cisplatin mice (P&lt;0.01, Figure 1) could be indicative of hematotoxicity or due to systemic failure. Comparison of the baseline SPECT/CT (day 0) images compared to the scans after treatment (day 7) corroborated our results that there was a marked increase in 99mTc-Duramycin in non-target organs than chlorambucil and sham control mice. Conclusions: Cisplatin shows significantly increased accumulation of 99mTc-Duramycin, an apoptosis imaging agent, in the small intestines and lungs in a preclinical wildtype mouse model when compared to chlorambucil and mice treated with saline using the same treatment regime. An evaluation is currently underway with a second cohort of mice (n=2 per group) with the same drug protocol that will be sacrificed for IHC analysis of selected organs.