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Abstract
The prognosis of differentiated thyroid cancer (DTC) is excellent, which is mainly due to the high therapeutic efficacy of radioactive iodine (RAI) therapy as well as indolent nature of thyroid cancer itself. Although most patients with DTC are well treated with RAI therapy, a certain number of patients have been suffered from refractoriness to RAI therapy. To overcome refractoriness, many alternative treatments have been investigated, and they could be classified based on the mechanisms of action; redifferentiation drug and molecular targeted drug. Not only redifferentiated drugs but also molecular targeted drugs could induce differentiation of thyroid cancer cells. Consequently, alternative treatments allowing tumor cells of RAI avidity followed by RAI therapy could utilize a synergistic effect of both therapies. Combined RAI therapy is expected to improve therapeutic effects and prognoses of RAI refractory thyroid cancers.
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Fig. 1.
Mechanisms of re-differentiation drugs. (A) In the absence of ligands, histone deacetylase (HDAC) containing complexes that are tethered through corepressors (CoR) bind to the heterodimers (RAR-RXR or PPAR-RXR) repress the transcription of target genes that are regulated by responsive elements (RARE or PRRE) in their promoters. (B) Binding of ligands (RA or PPAR γ agonist) destablizes the CoR-binding interface and induces allosteric changes in the ligand binding domain (LBD), which results in the formation of co-activators (CoA) and histone acetyltransferase (HAT) complexes. These series of conformational changes of the heterdimers activate the transcription of target genes. CoA: coactivator, CoR: corepressor, DBD: DNA binding domain, HAT: histone acetyltransferase, HDAC: histone deacetylase, LBD: ligand binding domain, PPAR: peroxisome proliferator activated receptor, PRRE: PPAR responsive element, RA: retinoic acid, RAR: retinoid acid receptor, RARE: RA responsive element, RXR: rexinoid receptor.
Fig. 2.
Combined radioactive iodine therapy with retinoic acid. No radioactive iodine (RAI) uptake was seen on the previous post-therapy scan (left). After retinoic acid treatment, RAI uptake was restored in the mediastinum (black arrow) and liver (white arrow) on the post-therapy scan (right).
Table 1.
Comparison of RAI-refractory thyroid cancer criteria
| RAI-refractory thyroid cancer | Ref. |
|---|---|
| 1. Presence of one target lesion without iodine uptake | 10 |
| (1) ≥One measurable lesion as measuared by CT or MR | |
| (2) Disease progression⋆ within 14 months | |
| 2. Patients whose tumors had iodine uptake | |
| At least one of the following criteria | |
| (1) Single RAI (≥37 MBq); disease progresssion⋆ within the previous 16 months | |
| (2) Multiple RAI (the last RAI>16 months ago); disease progression⋆ after each of 2 RAI Tx. (≥37 MBq) administered within 16 months of each other | |
| (3) A cumulative RAI dose of ≥22 GBq | |
| At least one of the following criteria | 11 |
| RAI non-avid metastatic lesion voidng on Dx. RAI scan upt to 2 years | |
| RAI avid metastatic lesion stable in size or progression⋆ despite of RAI therapy within 6 months | |
| FDG-avid lesion on PET |
Table 2.
Re-differentiation drugs
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