Nephroprotective effects of enalapril after [177Lu]-DOTATATE therapy using serial renal scintigraphies in a murine model of radiation-induced nephropathy

Ilhan, Harun; Wang, Hao; Gildehaus, Franz-Josef; Wängler, Carmen; Herrler, Tanja; Todica, Andrei; Schlichtiger, Julia; Cumming, Paul; Bartenstein, Peter; Hacker, Marcus; Haug, Alexander

doi:10.1186/s13550-016-0219-2

Cited by 10 publications

(6 citation statements)

References 37 publications

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“…Results of the scans at week one, six and eleven are not shown. As described previously, preserved renal function is observed by a fast and steep increase of [ 99m Tc]Tc-MAG3 in the kidneys with rapid excretion as well as preserved FUR values comparable to baseline [16,17]. The renal curve in group 1 (placebo) is almost unchanged compared to baseline.…”

Section: Bun Creatinine and Blood Count During Follow-upsupporting

confidence: 60%

“…[ 99m Tc]Tc-MAG3-scintigraphy was performed as described in previously published protocols [14][15][16][17]. Inhalational anaesthesia with 2.0% of isoflurane in pure oxygen was induced and maintained with a concentration of 1.5%.…”

Section: Renal Scintigraphymentioning

confidence: 99%

“…P(0) was obtained by extrapolating backwards, using a mono-exponential fit of P(t). The figures k l and k r are the slopes of the linear uptake (LU) segment of the Patlak-Rutland (PR) plots for the left and right kidneys [17].…”

Section: Renal Scintigraphymentioning

confidence: 99%

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Toxicity of a combined therapy using the mTOR-inhibitor everolimus and PRRT with [177Lu]Lu-DOTA-TATE in Lewis rats

Zellmer¹,

Yen

Kaiser³

et al. 2020

EJNMMI Res

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Purpose: Peptide receptor radionuclide therapy (PRRT) with [ 177 Lu]Lu-DOTA 0 ,TYR 3 -octreotate ([ 177 Lu]Lu-DOTA-TATE) and the mechanistic target of rapamycin (mTOR) inhibitor everolimus are both approved for the treatment of neuroendocrine tumours (NET). However, tumour progression is still frequent, and treatment strategies need further improvement. One possible approach could be to combine different therapy options. In this study, we investigated the toxicity of a combined treatment with everolimus and [ 177 Lu]Lu-DOTA-TATE in female Lewis rats. Methods: Animals received 200 MBq of [ 177 Lu]Lu-DOTA-TATE once and/or 5 mg/kg body weight everolimus or placebo weekly for 16 weeks and were divided into four groups (group 1, placebo; group 2, everolimus; group 3, placebo + [ 177 Lu]Lu-DOTA-TATE; group 4, everolimus + [ 177 Lu]Lu-DOTA-TATE). Blood levels of creatinine and blood urea nitrogen (BUN) were assessed weekly to monitor nephrotoxicity, and a full blood count was performed at the time of euthanasia to monitor myelotoxicity. Additionally, renal function was analysed by sequential [ 99m Tc]Tcmercaptoacetyltriglycine ([ 99m Tc]Tc-MAG3) scintigraphies. Histopathological examination was performed in all the kidneys using a standardized renal damage score (RDS). Results: Rats receiving everolimus showed a significantly lower increase in creatinine levels than those receiving placebo. Everolimus therapy reduced white blood count significantly, which was not observed for [ 177 Lu]Lu-DOTA-TATE. Functional renal scintigraphies using [ 99m Tc]Tc-MAG3 showed a compromised initial tracer uptake after PRRT and slower but still preserved excretion after everolimus. Histology showed no significant RDS differences between groups. Conclusion: Renal scintigraphy is a highly sensitive tool for the detection of renal function impairment after a combination of everolimus and PRRT. Additional treatment with everolimus does not increase renal and haematological toxicity of PRRT with [ 177 Lu]Lu-DOTA-TATE.

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Section: Bun Creatinine and Blood Count During Follow-upsupporting

confidence: 60%

Section: Renal Scintigraphymentioning

confidence: 99%

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Toxicity of a combined therapy using the mTOR-inhibitor everolimus and PRRT with [177Lu]Lu-DOTA-TATE in Lewis rats

Zellmer¹,

Yen

Kaiser³

et al. 2020

EJNMMI Res

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“…Radiolabeling of 177 Lu-DOTATATE was performed according to previously described protocols [16]. No-carrier added 177 Lutetium was obtained from Isotope Technologies Garching GmbH (Garching, Germany), DOTA 0 ,TYR 3 -octreotate was obtained from ABX advanced biochemical compounds (Dresden, Germany).…”

Section: Methodsmentioning

confidence: 99%

Salvage PRRT with 177Lu-DOTA-octreotate in extensively pretreated patients with metastatic neuroendocrine tumor (NET): dosimetry, toxicity, efficacy, and survival

et al. 2019

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Background NETTER-1 trial demonstrated high efficacy and low toxicity of four cycles of Peptide Receptor Radionuclide Therapy (PRRT) in patients with metastasized NET. The present study evaluates the outcome of further PRRT cycles in the so called salvage setting in patients after initial response to four therapy cycles and later progression. Methods Thirty five patients (pat.) (25 male, 10 female, 63 ± 9 years) with progressive, metastasized NET (23 small intestinal, 5 lung, 4 CUP, 1 rectal, 1 gastric and 1 paraganglioma) were included. All patients previously received 4 PRRT cycles with 177 Lu-DOTATATE and showed initial response. SPECT based dosimetry was applied to determine kidney and tumor doses. Therapy response was evaluated using 68 Ga-DOTATATE PET/CT (with high dose CT), CT alone or MRI (RECIST 1.1), toxicity was defined using CTCAE 5.0 criteria. 99m Tc99-MAG3 scintigraphy was used to assess potential renal tubular damage. Progression free survival (PFS) and Overall survival (OS) analysis was performed with the Kaplan-Meier-method. Results The median PFS after initial PRRT was 33 months (95% CI: 30–36). The mean cumulative dose for including salvage PRRT was 44 GBq (range 33.5–47). One pat. (2.9%) showed grade 3 hematotoxicity. Kidney dosimetry revealed a mean cumulative kidney dose after a median of 6 PRRT cycles of 23.8 Gy. No grade 3 / 4 nephrotoxicity or relevant decrease in renal function was observed. Follow-up imaging was available in 32 patients after salvage therapy. Best response according to RECIST 1.1. was PR in one patient (3.1%), SD in 26 patients (81.3%) and PD in 5 patients (15.6%). PFS after salvage therapy was 6 months (95% CI: 0–16; 8 patients censored). Mean OS after initial PRRT was 105 months (95% CI: 92–119) and 51 months (95% CI: 41–61) after start of salvage therapy. Median OS was not reached within a follow-up of 71 months after initial PRRT and 25 months after start of salvage PRRT, respectively. Conclusions Salvage therapy with 177 Lu-DOTATATE is safe and effective even in patients with extensive previous multimodal therapies during disease progression and represents a feasible and valuable therapy option for progressive NET. Electronic supplementary material The online version of this article (10.1186/s12885-019-6000-y) contains supplementary material, which is available to authorized users.

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“…More recently, another radical scavenger, α1-microglobulin, was used to prevent PRRT-induced nephrotoxicity in mice [ 50 ]. The renin-angiotensin system has been implicated in the development of radiation-induced nephrotoxicity, and administration of the angiotensin-converting enzyme inhibitor, enalapril, for 3 months after PRRT mitigated renal toxicity in mice [ 51 ]. To date, radioprotective agents have not been clinically examined in the setting of PRRT.…”

Section: Strategies To Mitigate Radiation-induced Nephrotoxicitymentioning

confidence: 99%

Application of Cleavable Linkers to Improve Therapeutic Index of Radioligand Therapies

Lau¹,

Lee

Rousseau³

et al. 2022

Molecules

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Radioligand therapy (RLT) is an emergent drug class for cancer treatment. The dose administered to cancer patients is constrained by the radiation exposure to normal tissues to maintain an appropriate therapeutic index. When a radiopharmaceutical or its radiometabolite is retained in the kidneys, radiation dose deposition in the kidneys can become a dose-limiting factor. A good exemplar is [177Lu]Lu-DOTATATE, where patients receive a co-infusion of basic amino acids for nephroprotection. Besides peptides, there are other classes of targeting vectors like antibody fragments, antibody mimetics, peptidomimetics, and small molecules that clear through the renal pathway. In this review, we will review established and emerging strategies that can be used to mitigate radiation-induced nephrotoxicity, with a focus on the development and incorporation of cleavable linkers for radiopharmaceutical designs. Finally, we offer our perspectives on cleavable linkers for RLT, highlighting future areas of research that will help advance the technology.

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Nephroprotective effects of enalapril after [177Lu]-DOTATATE therapy using serial renal scintigraphies in a murine model of radiation-induced nephropathy

Cited by 10 publications

References 37 publications

Toxicity of a combined therapy using the mTOR-inhibitor everolimus and PRRT with [177Lu]Lu-DOTA-TATE in Lewis rats

Toxicity of a combined therapy using the mTOR-inhibitor everolimus and PRRT with [177Lu]Lu-DOTA-TATE in Lewis rats

Salvage PRRT with 177Lu-DOTA-octreotate in extensively pretreated patients with metastatic neuroendocrine tumor (NET): dosimetry, toxicity, efficacy, and survival

Application of Cleavable Linkers to Improve Therapeutic Index of Radioligand Therapies

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