TY - JOUR
T1 - Sex as a biologic variable in preclinical imaging research
T2 - Initial Observations with 18 F-FLT
AU - Chan, Szeman Ruby
AU - Salem, Kelley
AU - Jeffery, Justin
AU - Powers, Ginny L.
AU - Yan, Yongjun
AU - Shoghi, Kooresh I.
AU - Mahajan, Aparna M.
AU - Fowler, Amy M.
N1 - Funding Information:
MB-231humanbreastcancerxenografts.Ki-67expressionwasassayed A rising concern from the National Institutes of Health is the 18byimmunohistochemistry.PET/CTimagingwasperformedtovisu- importance of including sex as a biologic variable in animal studies 18alize F-FLT biodistribution and to determine pharmacokinetics. and human clinical trials (1). Women were not required to be in-cle,heart,kidney,andboneinfemalethanmalemice.Pharmaco-Results:GreaterF-FLTactivitywasobservedinblood,liver,mus- cluded as subjects in clinical research until the Revitalization Act of kineticanalysisdemonstratedhigherearlyrenal18F-FLTactivityand 1993, and consideration of sex as an experimental variable did not greateraccumulationof18F-FLT in the urinary bladder in male than extend to federally funded preclinical work until 2014. This policy female mice. The differential pattern of 18F-FLT biodistribution be- is part of a broader goal to increase reproducibility and transparency tween the sexes seen with 18F-FLT was not observed with 18F-FDG. between research studies and to ensure scientific rigor.
Funding Information:
This work was supported by grants from the NCI (U01CA141541-01) and the Mallinckrodt Institute of Radiology at Washington University (MIR 11-037). Kooresh Shoghi is supported by grants U24CA209837 and U54CA199092 from the NCI. Funding was also provided to Amy Fowler through the University of Wisconsin Institute of Clinical and Translational Research KL2 Scholar Award (KL2TR000428). Facilities and services were provided by the University of Wisconsin Carbone Cancer Center (UWCCC) Small Animal Imaging Facility, Experimental Pathology Laboratory, and the Translational Research Initiatives in Pathology Laboratory (P30 CA014520). No other potential conflict of interest relevant to this article was reported.
Publisher Copyright:
COPYRIGHT © 2018 by the Society of Nuclear Medicine and Molecular Imaging.
PY - 2018/5/1
Y1 - 2018/5/1
N2 - The study objective was to investigate whether sex influences 3′-deoxy-3′- 18 F-fluorothymidine ( 18 F-FLT) uptake and tissue distribution in mouse models of cancer. Methods: 18 F-FLT biodistribution was measured in 3 strains of male and female mice (129S6/SvEv, athymic nude, and BALB/c). 18 F-FDG biodistribution was measured for comparison. 18 F-FLT uptake was also measured in female 129S6/SvEv mice bearing estrogen-dependent SSM3 mouse mammary tumors, male athymic nude mice bearing androgen-dependent CWR22 prostate cancer xenografts, and male and female athymic nude mice bearing estrogen-independent MDA-MB-231 human breast cancer xenografts. Ki-67 expression was assayed by immunohistochemistry. PET/CT imaging was performed to visualize 18 F-FLT biodistribution and to determine pharmacokinetics. Results: Greater 18 F-FLT activity was observed in blood, liver, muscle, heart, kidney, and bone in female than male mice. Pharmaco-kinetic analysis demonstrated higher early renal 18 F-FLT activity and greater accumulation of 18 F-FLT in the urinary bladder in male than female mice. The differential pattern of 18 F-FLT biodistribution between the sexes seen with 18 F-FLT was not observed with 18 F-FDG. Increased tumoral 18 F-FLT uptake compared with muscle was observed in both the SSM3 mammary tumors (2.4 ± 0.17 vs. 1.6 ± 0.14 percentage injected dose [%ID]/g at 2 h after injection, P = 0.006) and the CWR22 prostate cancer xenografts (0.34 ± 0.08 vs. 0.098 ± 0.033 %ID/g at 2 h after injection, P = 0.03). However, because of higher nonspecific muscle uptake in female mice, tumor-to-muscle uptake ratios were greater for CWR22 tumors than for SSM3 tumors (4.2 ± 0.78 vs. 1.5 ± 0.049 at 2 h after injection, P = 0.008). Sex-dependent differences in 18 F-FLT uptake were also observed for MDA-MB-231 xenografts (tumor-to-muscle ratio, 7.2 ± 0.9 for female vs. 16.9 ± 8.6 for male, P = 0.039). Conversely, greater tumoral Ki-67 staining was observed in female mice (71% ± 3% for female vs. 54% ± 2% for male, P = 0.009), and this finding more closely matched the relative differences in absolute 18 F-FLT tumor uptake values (4.5 ± 0.99 %ID/g for female vs. 1.9 ± 0.30 %ID/g for male, P = 0.03). Conclusion: Depending on whether female or male mice are used, differences in biodistribution and nonspecific tissue uptake can adversely affect quantitative measures of 18 F-FLT uptake. Thus, sex is a potential variable to consider in defining quantitative imaging metrics using 18 F-FLT to assess tumor proliferation.
AB - The study objective was to investigate whether sex influences 3′-deoxy-3′- 18 F-fluorothymidine ( 18 F-FLT) uptake and tissue distribution in mouse models of cancer. Methods: 18 F-FLT biodistribution was measured in 3 strains of male and female mice (129S6/SvEv, athymic nude, and BALB/c). 18 F-FDG biodistribution was measured for comparison. 18 F-FLT uptake was also measured in female 129S6/SvEv mice bearing estrogen-dependent SSM3 mouse mammary tumors, male athymic nude mice bearing androgen-dependent CWR22 prostate cancer xenografts, and male and female athymic nude mice bearing estrogen-independent MDA-MB-231 human breast cancer xenografts. Ki-67 expression was assayed by immunohistochemistry. PET/CT imaging was performed to visualize 18 F-FLT biodistribution and to determine pharmacokinetics. Results: Greater 18 F-FLT activity was observed in blood, liver, muscle, heart, kidney, and bone in female than male mice. Pharmaco-kinetic analysis demonstrated higher early renal 18 F-FLT activity and greater accumulation of 18 F-FLT in the urinary bladder in male than female mice. The differential pattern of 18 F-FLT biodistribution between the sexes seen with 18 F-FLT was not observed with 18 F-FDG. Increased tumoral 18 F-FLT uptake compared with muscle was observed in both the SSM3 mammary tumors (2.4 ± 0.17 vs. 1.6 ± 0.14 percentage injected dose [%ID]/g at 2 h after injection, P = 0.006) and the CWR22 prostate cancer xenografts (0.34 ± 0.08 vs. 0.098 ± 0.033 %ID/g at 2 h after injection, P = 0.03). However, because of higher nonspecific muscle uptake in female mice, tumor-to-muscle uptake ratios were greater for CWR22 tumors than for SSM3 tumors (4.2 ± 0.78 vs. 1.5 ± 0.049 at 2 h after injection, P = 0.008). Sex-dependent differences in 18 F-FLT uptake were also observed for MDA-MB-231 xenografts (tumor-to-muscle ratio, 7.2 ± 0.9 for female vs. 16.9 ± 8.6 for male, P = 0.039). Conversely, greater tumoral Ki-67 staining was observed in female mice (71% ± 3% for female vs. 54% ± 2% for male, P = 0.009), and this finding more closely matched the relative differences in absolute 18 F-FLT tumor uptake values (4.5 ± 0.99 %ID/g for female vs. 1.9 ± 0.30 %ID/g for male, P = 0.03). Conclusion: Depending on whether female or male mice are used, differences in biodistribution and nonspecific tissue uptake can adversely affect quantitative measures of 18 F-FLT uptake. Thus, sex is a potential variable to consider in defining quantitative imaging metrics using 18 F-FLT to assess tumor proliferation.
UR - http://www.scopus.com/inward/record.url?scp=85046449737&partnerID=8YFLogxK
U2 - 10.2967/jnumed.117.199406
DO - 10.2967/jnumed.117.199406
M3 - Article
C2 - 29217733
AN - SCOPUS:85046449737
SN - 0161-5505
VL - 59
SP - 833
EP - 838
JO - Journal of Nuclear Medicine
JF - Journal of Nuclear Medicine
IS - 5
ER -