Abstract
Simple SummaryThe peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTA-octreotate (LuTate) is recommended for neuroendocrine tumors (NETs) which overexpress somatostatin receptors (SSTR). A combination of LuTate with chemotherapy improves its objective response in NET patients, and here we characterized chemotherapy-induced upregulation of SSTR2 receptors as a cause for this improved response to LuTate. Using multiple NET and non-NET cell lines, we examined the SSTR2 expression for up to 7 days after exposure to drugs and its effect on LuTate uptake and cell proliferation. We report that the exposure to varying doses of chemotherapeutic drugs such as temozolomide for 24 h or 5 days results in upregulation of SSTR2 receptors between 3–7 days. This effect is more pronounced in low SSTR2 expressing BON-1 cells than in high SSTR2 expressing NCI-H727 or non-NET cancer or non-cancer cells. Thus, a properly-timed pre-treatment with low doses of chemotherapy could improve therapeutic efficacy of LuTate in NET patients.The peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTA-octreotate (LuTate) is recommended for different types of neuroendocrine tumors (NETs) which overexpress somatostatin receptors (SSTR). A combination with chemotherapy improves objective response to LuTate in NET patients and here we characterized chemotherapy-induced upregulation of SSTR2 receptors as a cause for this improved response to LuTate. The NET cell lines with low (BON-1) or relatively high (NCI-H727) SSTR2-expression levels, and non-NET cancer and normal cells were treated with chemotherapeutic drugs and assessed for upregulation of SSTR2. We report that an exposure to low or high doses of drugs, such as temozolomide for 24 h or 5 day results in upregulation of SSTR2 between 3–7 days, increased LuTate uptake and decreased rate of cell proliferation. This effect is at the level of SSTR2-mRNA and is more pronounced in low SSTR2 expressing BON-1 than in high SSTR2 expressing NCI-H727 or non-NET cancer or normal cells. Thus, a properly timed pre-treatment with low-dose chemotherapy could not only improve therapeutic efficacy of LuTate in NET patients who are presently eligible for PRRT, but also allow PRRT to be administered to patients with low SSTR-expressing NETs, who would otherwise not respond to this modality because of insufficient radiation delivery.
Highlights
Neuroendocrine tumors (NETs) are rare cancers derived from enterochromaffin cells of the diffuse neuroendocrine system
We have previously shown that the extent of intracellular uptake of LuTate after a 5-day exposure was commensurate with the expression levels of SSTR2 and SSTR5 [26]
In order to examine the cause for drug-induced increase in SSTR2 in BON-1 cells, we examined the abundance of mRNA for all five SSTR genes by qRT-PCR for 6 days after treatment with even lower dose (10 μM) of TEM (Figure 4A)
Summary
Neuroendocrine tumors (NETs) are rare cancers derived from enterochromaffin cells of the diffuse neuroendocrine system. They are most frequently observed in the gastrointestinal tract and bronchopulmonary system [1,2,3]. After progression on SSAs, or for more aggressive NETs with high proliferative index, other systemic options include targeted biotherapies such as everolimus or sunitinib, as well as chemotherapeutic drugs, such as temozolomide (TEM), streptozotocin (STZ) and 5-fluorouracil (5-FU) or its pro-drug form, capecitabine (CAP). Peptide receptor radionuclide therapy (PRRT) has emerged as another option for systemic therapy of NETs. PRRT involves use of SSA tagged with radionuclides, such as 111 In, 90 Y or 177 Lu to deliver targeted therapeutic internal radiation to NET cells [7]. PRRT involves use of SSA tagged with radionuclides, such as 111 In, 90 Y or 177 Lu to deliver targeted therapeutic internal radiation to NET cells [7]. 177 Lu-DOTA-octreotate (LuTate or 177 Lu-DOTATATE; Lutathera® ) is the preferred PRRT radiopharmaceutical to date due to its high affinity to SSTR2 and its optimal β-particle energy offering improved response rates over 111 In-based
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