[18F]FLT PET for non-invasive assessment of tumor sensitivity to chemotherapy: studies with experimental chemotherapy TP202377 in human cancer xenografts in mice.

Abstract

AIM:

3'-deoxy-3'-[¹⁸F]fluorothymidine ([18F]FLT) is a tracer used to assess cell proliferation in vivo. The aim of the study was to use [18F]FLT positron emission tomography (PET) to study non-invasively early anti-proliferative effects of the experimental chemotherapeutic agent TP202377 in both sensitive and resistant tumors.

METHODS:

Xenografts in mice from 3 human cancer cell lines were used: the TP202377 sensitive A2780 ovary cancer cell line (n = 8-16 tumors/group), the induced resistant A2780/Top216 cell line (n = 8-12 tumors/group) and the natural resistant SW620 colon cancer cell line (n = 10 tumors/group). In vivo uptake of [18F]FLT was studied at baseline and repeated 6 hours, Day 1, and Day 6 after TP202377 treatment (40 mg/kg i.v.) was initiated. Tracer uptake was quantified using small animal PET/CT.

RESULTS:

TP202377 (40 mg/kg at 0 hours) caused growth inhibition at Day 6 in the sensitive A2780 tumor model compared to the control group (P<0.001). In the A2780 tumor model TP202377 treatment caused significant decrease in uptake of [18F]FLT at 6 hours (-46%; P<0.001) and Day 1 (-44%; P<0.001) after treatment start compared to baseline uptake. At Day 6 uptake was comparable to baseline. Treatment with TP202377 did not influence tumor growth or [18F]FLT uptake in the resistant A2780/Top216 and SW620 tumor models. In all control groups uptake of [18F]FLT did not change. Ki67 gene expression paralleled [18F]FLT uptake.

CONCLUSION:

Treatment of A2780 xenografts in mice with TP202377 (single dose i.v.) caused a significant decrease in cell proliferation assessed by [18F]FLT PET after 6 hours. Inhibition persisted at Day 1; however, cell proliferation had returned to baseline at Day 6. In the resistant A2780/Top216 and SW620 tumor models uptake of [18F]FLT did not change after treatment. With [18F]FLT PET it was possible to distinguish non-invasively between sensitive and resistant tumors already 6 hours after treatment initiation.

• Authors: Mette Munk Jensen, Kamille Dumong Erichsen, Fredrik Björkling, Jacob Madsen, Peter Buhl Jensen, Maxwell Sehested, Liselotte Højgaard, Andreas Kjær
• Journal: PloS one (PLoS One) Vol. 7 Issue 11 Pg. e50618 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 23226334 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Dideoxynucleosides
• Indoles
• Ki-67 Antigen
• TP202377
• Thymidine Kinase
• thymidine kinase 1
• alovudine

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Biological Transport
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dideoxynucleosides (metabolism)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Indoles (pharmacology, therapeutic use)
• Ki-67 Antigen (genetics)
• Mice
• Ovarian Neoplasms (diagnostic imaging, drug therapy, pathology)
• Positron-Emission Tomography
• Thymidine Kinase (genetics)
• Time Factors
• Tomography, X-Ray Computed
• Treatment Failure
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays