Using Radiolabeled 3'-Deoxy-3'-18F-Fluorothymidine with PET to Monitor the Effect of Dexamethasone on Non-Small Cell Lung Cancer

Abstract

Non-small cell lung cancer (NSCLC) is a leading cause of cancer mortality in the United States, and pemetrexed-based therapies are regularly used to treat nonsquamous NSCLC. Despite widespread use, pemetrexed has a modest effect on progression-free survival, with varying efficacy between individuals. Recent work has indicated that dexamethasone, given to prevent pemetrexed toxicity, is able to protect a subset of NSCLC cells from pemetrexed cytotoxicity by temporarily suppressing the S phase of the cell cycle. Therefore, dexamethasone might block treatment efficacy in a subpopulation of patients and might be contributing to the variable response to pemetrexed. Methods: Differences in retention of the experimental PET tracer 3'-deoxy-3'-fluorothymidine (FLT) were used to monitor S-phase suppression by dexamethasone in NSCLC cell models, animals with tumor xenografts, and patients with advanced cancer. Results: Significant reductions in tracer uptake were observed after 24 h of dexamethasone treatment in NSCLC cell lines and xenograft models expressing high levels of glucocorticoid receptor α, coincident with pemetrexed resistance visualized by attenuation of the flare effect associated with pemetrexed activity. Two of 4 patients imaged in a pilot study with ¹⁸F-FLT PET after dexamethasone treatment demonstrated reductions in tracer uptake from baseline, with a variable response between individual tumor lesions. Conclusion:¹⁸F-FLT PET represents a useful method for the noninvasive monitoring of dexamethasone-mediated S-phase suppression in NSCLC and might provide a way to individualize chemotherapy in patients receiving pemetrexed-based regimens.

Keywords: FLT; PET; dexamethasone; imaging; lung cancer.

FIGURE 1.

Dexamethasone reduces ³H-FLT retention most in NSCLC cell lines with highest GRα expression. (A) GRα messenger RNA measured by RT-PCR. (B) Western blot showing total GR protein expression. (C) ³H-FLT in NSCLC cell lines after 24 and 48 h of dexamethasone treatment. Dex = dexamethasone; GAPDH = glyceraldehyde 3-phosphate dehydrogenase. *P < 0.01.

FIGURE 2.

Dexamethasone reduces ¹⁸F-FLT accumulation in mice bearing A549 tumors. (A) Representative images of animals treated with dexamethasone or control (saline). (B) Plot of SUV_max for tumors treated with dexamethasone or control. Dex = dexamethasone. *P < 0.01.

FIGURE 3.

Decline in ¹⁸F-FLT retention after dexamethasone treatment depends on GRα expression. (A) Representative pre- and postdexamethasone images of animals implanted with H1299 or H1299-GRα tumors (encircled). (B) Plot comparing SUV_max between H1299 and H1299-GRα tumors. Dex = dexamethasone. *P < 0.01.

FIGURE 4.

¹⁸F-FLT PET captures interlesion heterogeneity. ¹⁸F-FLT PET images are shown from patient with NSCLC at baseline and after 24 h of dexamethasone treatment. In nodal metastasis A, ¹⁸F-FLT uptake decreased by 64.7%. Tracer retention in lesions B, C, D, and E decreased by 13.7%, 33.1%, 18.1%, and 34.6%, respectively. Vertebral, sternal, and rib marrow activity was unchanged. Dex = dexamethasone.

FIGURE 5.

Pemetrexed increased ³H-FLT retention in NSCLC cell lines, but dexamethasone pretreatment abrogated this effect. Graph shows ³H-FLT uptake in NSCLC cells treated with vehicle (saline) or pemetrexed with and without dexamethasone pretreatment. Dex = dexamethasone. *P < 0.01.

FIGURE 6.

Pemetrexed-induced flare in ¹⁸F-FLT uptake is abolished with dexamethasone pretreatment in animal xenografts. (A) Representative images of mice bearing A549 tumors (encircled). (B) Plot showing effect of pemetrexed on ¹⁸F-FLT retention with and without dexamethasone pretreatment. Dex = dexamethasone. *P < 0.01.

FIGURE 7.

Eradication of pemetrexed-induced flare by dexamethasone occurs in GRα-dependent fashion. (A) Representative images of mice bearing H1299 or H1299-GRα tumors (encircled). (B) Plot showing effect of pemetrexed on ¹⁸F-FLT retention with and without dexamethasone pretreatment. Dex = dexamethasone. *P < 0.01.