[Show abstract][Hide abstract] ABSTRACT: The potential risk of recurrence and progression in patients with non-muscle-invasive bladder cancer necessitates followup by cystoscopy. The risk of progression to muscle-invasive bladder cancer is estimated based on the European Organisation of Research and Treatment of Cancer score, a combination of several clinicopathological variables. However, pathological assessment is not objective and reproducibility is insufficient. The use of molecular markers could contribute to the estimation of tumor aggressiveness. We recently demonstrated that methylation of GATA2, TBX2, TBX3, and ZIC4 genes could predict progression in Ta tumors. In this study, we aimed to validate the markers in a large patient set using DNA from formalin-fixed and paraffin-embedded tissue.
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 11/2014;
[Show abstract][Hide abstract] ABSTRACT: In this study we set out to investigate the clinically observed relationship between chronic obstructive pulmonary disease (COPD) and aortic aneurysms. We tested the hypothesis that an inherited deficiency of connective tissue might play a role in the combined development of pulmonary emphysema and vascular disease.
PLoS ONE 01/2014; 9(9):e106054. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hotspot mutations in the promoter of the gene coding for telomerase reverse transcriptase (TERT) have been described and proposed to activate gene expression.
To investigate TERT mutation frequency, spectrum, association with expression and clinical outcome, and potential for detection of recurrences in urine in patients with urothelial bladder cancer (UBC).
A set of 111 UBCs of different stages was used to assess TERT promoter mutations by Sanger sequencing and TERT messenger RNA (mRNA) expression by reverse transcription-quantitative polymerase chain reaction. The two most frequent mutations were investigated, using a SNaPshot assay, in an independent set of 184 non-muscle-invasive and 173 muscle-invasive UBC (median follow-up: 53 mo and 21 mo, respectively). Voided urine from patients with suspicion of incident UBC (n=174), or under surveillance after diagnosis of non-muscle-invasive UBC (n=194), was tested using a SNaPshot assay.
Association of mutation status with age, sex, tobacco, stage, grade, fibroblast growth factor receptor 3 (FGFR3) mutation, progression-free survival, disease-specific survival, and overall survival.
In the two series, 78 of 111 (70%) and 283 of 357 (79%) tumors harbored TERT mutations, C228T being the most frequent substitution (83% for both series). TERT mutations were not associated with clinical or pathologic parameters, but were more frequent among FGFR3 mutant tumors (p=0.0002). There was no association between TERT mutations and mRNA expression (p=0.3). Mutations were not associated with clinical outcome. In urine, TERT mutations had 90% specificity in subjects with hematuria but no bladder tumor, and 73% in recurrence-free UBC patients. The sensitivity was 62% in incident and 42% in recurrent UBC. A limitation of the study is its retrospective nature.
Somatic TERT promoter mutations are an early, highly prevalent genetic event in UBC and are not associated with TERT mRNA levels or disease outcomes. A SNaPshot assay in urine may help to detect UBC recurrences.
[Show abstract][Hide abstract] ABSTRACT: The ten-subunit transcription factor IIH (TFIIH) plays a crucial role in transcription and nucleotide excision repair (NER). Inactivating mutations in the smallest 8-kDa TFB5/TTDA subunit cause the neurodevelopmental progeroid repair syndrome trichothiodystrophy A (TTD-A). Previous studies have shown that TTDA is the only TFIIH subunit that appears not to be essential for NER, transcription, or viability. We studied the consequences of TTDA inactivation by generating a Ttda knock-out (Ttda(-/-) ) mouse-model resembling TTD-A patients. Unexpectedly, Ttda(-/-) mice were embryonic lethal. However, in contrast to full disruption of all other TFIIH subunits, viability of Ttda(-/-) cells was not affected. Surprisingly, Ttda(-/-) cells were completely NER deficient, contrary to the incomplete NER deficiency of TTD-A patient-derived cells. We further showed that TTD-A patient mutations only partially inactivate TTDA function, explaining the relatively mild repair phenotype of TTD-A cells. Moreover, Ttda(-/-) cells were also highly sensitive to oxidizing agents. These findings reveal an essential role of TTDA for life, nucleotide excision repair, and oxidative DNA damage repair and identify Ttda(-/-) cells as a unique class of TFIIH mutants.
[Show abstract][Hide abstract] ABSTRACT: PURPOSE: Bladder tumors of patients <20yr have a low incidence of genetic and epigenetic aberrations typically found in older patients. One of the most common epigenetic aberrations in human malignancies is DNA hypermethylation. Polycomb group (PcG) complexes play an important role during lineage choices in embryogenesis and their target genes are 12 times more likely to be methylated than non-PcG target genes. We hypothesized that methylation of PcG target genes is an early event in urothelial carcinogenesis and thus might be observed in young patients. MATERIALS AND METHODS: Patients (n=167) were stratified according to age into four groups: <20yr (n=14), 20-40yr (n=48), 40-60yr (n=47) and >60yr (n=58). Five PcG target genes identified by Kandimalla et al (MEIS1, ONECUT2, OTX1, PCDH7 and SOX21) were selected for methylation analysis. Methylation ratios were calculated by using the unmethylated and methylated signal. The outcome represented the fraction of methylated cells within one tumor. Genes with similar methylation ratios in all age groups were considered as potential bladder cancer initiating candidates. RESULTS: Three genes showed higher methylation ratios in tumors from older patients: ONECUT2 (p<0.001), SOX21 (p<0.001) and OTX1 (p<0.001). MEIS1 displayed similar methylation ratios in all groups. However the median methylation ratio was low. PCDH7 exhibited similar median methylation percentages in all age categories, i.e. <20yr 54%; 20-40yr 59%; 40-60yr 59%; >60yr 67% (p=0.1). CONCLUSIONS: Tumors from young patients showed less methylation for most markers. PDH7 showed high methylation ratios in all age categories and could therefore play an important role in early urothelial carcinogenesis.
The Journal of urology 01/2013; · 3.75 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Mammalian CLASPs are microtubule plus-end tracking proteins whose essential function as regulators of microtubule behavior has been studied mainly in cultured cells. We show here that absence of murine CLASP2 in vivo results in thrombocytopenia, progressive anemia, and pancytopenia, due to defects in megakaryopoiesis, in erythropoiesis, and in the maintenance of hematopoietic stem cell activity. Furthermore, microtubule stability and organization are affected upon attachment of Clasp2 knockout hematopoietic stem-cell-enriched populations, and these cells do not home efficiently toward their bone marrow niche. Strikingly, CLASP2-deficient hematopoietic stem cells contain severely reduced mRNA levels of c-Mpl, which encodes the thrombopoietin receptor, an essential factor for megakaryopoiesis and hematopoietic stem cell maintenance. Our data suggest that thrombopoietin signaling is impaired in Clasp2 knockout mice. We propose that the CLASP2-mediated stabilization of microtubules is required for proper attachment, homing, and maintenance of hematopoietic stem cells and that this is necessary to sustain c-Mpl transcription.
[Show abstract][Hide abstract] ABSTRACT: Neuronal degeneration is a hallmark of many DNA repair syndromes. Yet, how DNA damage causes neuronal degeneration and whether defects in different repair systems affect the brain differently is largely unknown. Here, we performed a systematic detailed analysis of neurodegenerative changes in mouse models deficient in nucleotide excision repair (NER) and transcription-coupled repair (TCR), two partially overlapping DNA repair systems that remove helix-distorting and transcription-blocking lesions, respectively, and that are associated with the UV-sensitive syndromes xeroderma pigmentosum (XP) and Cockayne syndrome (CS). TCR-deficient Csa(-/-) and Csb(-/-) CS mice showed activated microglia cells surrounding oligodendrocytes in regions with myelinated axons throughout the nervous system. This white matter microglia activation was not observed in NER-deficient Xpa(-/-) and Xpc(-/-) XP mice, but also occurred in Xpd(XPCS) mice carrying a point mutation (G602D) in the Xpd gene that is associated with a combined XPCS disorder and causes a partial NER and TCR defect. The white matter abnormalities in TCR-deficient mice are compatible with focal dysmyelination in CS patients. Both TCR-deficient and NER-deficient mice showed no evidence for neuronal degeneration apart from p53 activation in sporadic (Csa(-/-), Csb(-/-)) or highly sporadic (Xpa(-/-), Xpc(-/-)) neurons and astrocytes. To examine to what extent overlap occurs between both repair systems, we generated TCR-deficient mice with selective inactivation of NER in postnatal neurons. These mice develop dramatic age-related cumulative neuronal loss indicating DNA damage substrate overlap and synergism between TCR and NER pathways in neurons, and they uncover the occurrence of spontaneous DNA injury that may trigger neuronal degeneration. We propose that, while Csa(-/-) and Csb(-/-) TCR-deficient mice represent powerful animal models to study the mechanisms underlying myelin abnormalities in CS, neuron-specific inactivation of NER in TCR-deficient mice represents a valuable model for the role of NER in neuronal maintenance and survival.
[Show abstract][Hide abstract] ABSTRACT: Medial degeneration is a key feature of aneurysm disease and aortic dissection. In a murine aneurysm model we investigated the structural and functional characteristics of aortic wall degeneration in adult fibulin-4 deficient mice and the potential therapeutic role of the angiotensin (Ang) II type 1 (AT(1)) receptor antagonist losartan in preventing aortic media degeneration. Adult mice with 2-fold (heterozygous Fibulin-4(+/R)) and 4-fold (homozygous Fibulin-4(R/R)) reduced expression of fibulin-4 displayed the histological features of cystic media degeneration as found in patients with aneurysm or dissection, including elastin fiber fragmentation, loss of smooth muscle cells, and deposition of ground substance in the extracellular matrix of the aortic media. The aortic contractile capacity, determined by isometric force measurements, was diminished, and was associated with dysregulation of contractile genes as shown by aortic transcriptome analysis. These structural and functional alterations were accompanied by upregulation of TGF-β signaling in aortas from fibulin-4 deficient mice, as identified by genome-scaled network analysis as well as by immunohistochemical staining for phosphorylated Smad2, an intracellular mediator of TGF-β. Tissue levels of Ang II, a regulator of TGF-β signaling, were increased. Prenatal treatment with the AT(1) receptor antagonist losartan, which blunts TGF-β signaling, prevented elastic fiber fragmentation in the aortic media of newborn Fibulin-4(R/R) mice. Postnatal losartan treatment reduced haemodynamic stress and improved lifespan of homozygous knockdown fibulin-4 animals, but did not affect aortic vessel wall structure. In conclusion, the AT(1) receptor blocker losartan can prevent aortic media degeneration in a non-Marfan syndrome aneurysm mouse model. In established aortic aneurysms, losartan does not affect aortic architecture, but does improve survival. These findings may extend the potential therapeutic application of inhibitors of the renin-angiotensin system to the preventive treatment of aneurysm disease.
PLoS ONE 01/2011; 6(8):e23411. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We imaged the protease activity of matrix metalloproteinases (MMPs) upregulated during aneurysm formation, using protease-activatable near-infrared fluorescence probes. We tested whether these protease-activatable sensors can directly report the in vivo activity of the key biomarkers in aneurysm, using our genetically modified fibulin-4 mouse models for aneurysm formation. Mice homozygous for the fibulin-4 reduced-expression allele (fibulin-4(R/R)) show dilatation of the ascending aorta and a tortuous, stiffened aorta resulting from disorganized elastic fiber networks. Strikingly, even a moderate reduction in expression of fibulin-4 in the heterozygous fibulin-4(+/R) mice occasionally results in modest aneurysm formation.
Aorta transcriptome and protein expression analysis of fibulin-4(+/R) and fibulin-4(R/R) animals identified excessive transforming growth factor-β signaling as the critical event in the pathogenesis of aneurysm formation. To determine whether a perturbed elastin lamellar structure arose from induction of transforming growth factor-β-regulated MMPs, we performed gelatin zymography and used a protease-activatable near-infrared fluorescence probe to monitor and quantify MMP upregulation in animals, using various in vivo optical imaging modules and coregistration of the fluorescence signal with CT images of the same animals. Gelatin zymography demonstrated a significant increase in the presence of the active form of MMP-9 in the aortic arch of fibulin-4(R/R) mice. In vivo analysis of MMP upregulation using the near-infrared fluorescence probe and subsequent isosurface concentration mapping from reconstructed tomographic images from fibulin-4(+/R) and fibulin-4(R/R) mice revealed a graded increase in activation of MMPs within the aneurysmal lesions.
We aimed to develop molecular imaging procedures for faster, earlier, and easier recognition of aortic aneurysms. We show that in vivo coregistration of MMP activity by noninvasive tomographic imaging methods allows the detection of increased MMP activity, even before the aneurysm has actually formed.
[Show abstract][Hide abstract] ABSTRACT: We determined the renal radiation dose of a series of (111)In-labeled peptides using animal SPECT. Because the animals' health deteriorated, renal toxicity was assessed.
Wild-type and megalin-deficient mice were imaged repeatedly at 3- to 6-wk intervals to quantify renal retention after injection of 40-50 MBq of (111)In-diethylenetriaminepentaacetic acid-labeled peptides (octreotide, exendin, octreotate, neurotensin, and minigastrin analogs), and the absorbed kidney radiation doses were estimated. Body weight, renal function parameters, and renal histology were determined at 16-20 wk after the first scan and compared with those in naive animals.
Because of high renal retention, (111)In-diethylenetriaminepentaacetic acid-exendin-4 scans resulted in a 70-Gy kidney radiation dose in wild-type mice. Megalin-deficient kidneys received 20-40 Gy. The other peptides resulted in much lower renal doses. Kidney function monitoring indicated renal damage in imaged animals.
Micro-SPECT enables longitudinal studies in 1 animal. However, long-term nephrotoxic effects may be induced after high renal radiation doses, even with (111)In-labeled radiotracers.
Journal of Nuclear Medicine 06/2010; 51(6):973-7. · 5.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The molecular characteristics and the clinical disease course of bladder cancer (BC) in young patients remain largely unresolved. All patients are monitored according to an intensive surveillance protocol and we aim to gain more insight into the molecular pathways of bladder tumors in young patients that could ultimately contribute to patient stratification, improve patient quality of life and reduce associated costs. We also determined whether a biomarker-based surveillance could be feasible.
We report a unique case of a 26-year-old Caucasian male with recurrent non-muscle invasive bladder tumors occurring at a high frequency and analyzed multiple tumors (maximal pTaG2) and urine samples of this patient. Analysis included FGFR3 mutation detection, FGFR3 and TP53 immunohistochemistry, mircosatellite analysis of markers on chromosomes 8, 9, 10, 11 and 17 and a genome wide single nucleotide polymorphism-array (SNP). All analyzed tumors contained a mutation in FGFR3 and were associated with FGFR3 overexpression. None of the tumors showed overexpression of TP53. We found a deletion on chromosome 9 in the primary tumor and this was confirmed by the SNP-array that showed regions of loss on chromosome 9. Detection of all recurrences was possible by urinary FGFR3 mutation analysis.
Our findings would suggest that the BC disease course is determined by not only a patient's age, but also by the molecular characteristics of a tumor. This young patient contained typical genetic changes found in tumors of older patients and implies a clinical disease course comparable to older patients. We demonstrate that FGFR3 mutation analysis on voided urine is a simple non-invasive method and could serve as a feasible follow-up approach for this young patient presenting with an FGFR3 mutant tumor.
[Show abstract][Hide abstract] ABSTRACT: Heparan sulfate glycosaminoglycans (HS-GAGs) are not only the structural elements of tissue architecture but also regulate the bioavailability and transduction pathways of heparan sulfate-bound polypeptides released by cells or the extracellular matrix. Heparan sulfate-bound polypeptides include inflammatory mediators, chemokines, angiogenic factors, morphogens, and growth-promoting factors that induce cell migration, proliferation, and differentiation in wound healing. OTR4120, a polymer engineered to mimic the properties of HS-GAGs, is used to replace the natural HS-GAGs that are degraded during wound repair, and enhance the tissue regeneration by preserving the cellular microenvironment and the endogenous signals needed for tissue regeneration. We previously demonstrated that OTR4120 treatment had a long-term effect on increasing breaking strength and vasodilation in healing rat full-thickness excisional wounds. The present study investigates the underlying mechanisms of the effects of OTR4120 treatment in improving the quality of cutaneous wound repair. We found that OTR4120 treatment stimulated inflammation resolution and increased neovascularization. OTR4120 treatment also promoted epidermal migration and proliferation during reepithelialization. Moreover, the granulation tissue formation and collagen maturation were improved in OTR4120-treated wounds. Three months after wounding, the effects of OTR4120 treatment on vascularization and inflammation resolution were normalized, except for an improved neodermis. We conclude that OTR4120 is a potential matrix therapeutic agent that ensures the quality of normal cutaneous wound repair and may restore impaired wound healing characterized by deficient angiogenesis and prolonged inflammation.
Wound Repair and Regeneration 10/2009; 17(6):840-52. · 2.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Introduction. External beam radiotherapy for prostate cancer leads to erectile dysfunction in 36%–43% of patients. The underlying mechanism is largely unknown, although some clinical studies suggest that the arterial supply to the corpora cavernosa is responsible. Two animal experimental studies reported on the effects of a single fraction of prostate irradiation on the penile structures. However, irradiation in multiple fractions is more representative of the actual clinical treatment.Aim. The present prospective, controlled study was initiated to investigate the effect of fractionated prostate irradiation on the arteries of the corpora cavernosa.Main Outcome Measures. Histological evaluation of the penile tissue in comparison with control rats at 2, 4, and 9 weeks after irradiation.Methods. The prostate of twelve rats was treated with external beam radiation in 5 daily fractions of 7.4 gray. Three control rats were treated with sham irradiation. Prostatic and penile tissue was evaluated for general histology (hematoxylin–eosin). The penile tissue was further evaluated after combined staining for collagen (resorcin fuchsin) and α-smooth muscle actin (SMA) (Biogenex).Results. The prostate showed adequate irradiation with fibrosis occurring at 9 weeks after irradiation. The corpora cavernosa showed arteries that had developed loss of smooth muscle cells expressing SMA, thickening of the intima, and occlusions. All the control rats maintained normal anatomy.Conclusion. This is the first animal experimental study that demonstrates changes in the arteries of the corpora cavernosa after fractionated irradiation to the prostatic area. The preliminary data suggests that erectile dysfunction after radiotherapy might be caused by radiation damage to the arterial supply of the corpora cavernosa. van der Wielen GJ, Vermeij M, de Jong BWD, Schuit M, Marijnissen J, Kok DJ, van Weerden WM, and Incrocci L. Changes in the penile arteries of the rat after fractionated irradiation of the prostate: A pilot study. J Sex Med 2009;6:1908–1913.
Journal of Sexual Medicine 06/2009; 6(7):1908 - 1913. · 3.51 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Non-muscle invasive bladder cancers (NMI-BCs) represent 75% of bladder cancers upon presentation. After removal of the primary tumour by transurethral resection, multiple recurrences continue to develop in 70% of patients. Consequently, prolonged and costly surveillance by cystoscopy is required. Mutations in the FGFR3 oncogene are common in NMI-BCs and are associated with a lower chance of progression to muscle-invasive disease. Here we analysed the consistency of FGFR3 mutations in primary and recurrent tumours. This knowledge is of crucial importance if FGFR3 mutation analysis on urinary cells is to be used as an alternative for cystoscopical surveillance. To this end, we monitored the disease process and FGFR3 mutation status of primary and recurrent tumours in 118 patients with NMI-BC. During median follow-up of 8.8 years, these patients underwent 2133 cystoscopies and 80 patients developed 414 recurrences. FGFR3 mutations were equally prevalent in primary and recurrent tumours (63%). Patients can have different types of FGFR3 mutations in different tumours. Recurrence risk was not significantly different for patients with a mutant or wild-type primary tumour. Recurrence rates varied widely between patients but were constant for a patient and were unrelated to FGFR3 status. In the mutant patient group, in contrast to the wild-type group, recurrences continued to develop after 10 years. In 81% of the recurrences of patients with a mutant primary tumour, a mutation was found. Moreover, recurrences in this patient group were of lower stage and grade than those of patients with a wild-type primary tumour (p < 0.001). These results suggest that surveillance by FGFR3 mutation analysis on voided urine in combination with a reduced cystoscopy frequency of patients presenting with an FGFR3 mutant tumour is worth investigating.
The Journal of Pathology 12/2008; 218(1):104-12. · 7.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Regressions of metastatic solid tumors after allogeneic human leukocyte antigen (HLA)-matched stem cell transplantation (SCT) are often associated with detrimental graft-versus-host disease (GVHD). The graft-versus-host reaction of the HLA-matched donor is directed mainly against the multiple mismatched minor histocompatibility antigens (mHags) of the patient. mHags are strong HLA-restricted alloantigens with differential tissue distribution. Ubiquitously expressed mHags are the prime in situ targets of GVHD. The mHag HA-1 is hematopoiesis restricted, but displays additionally an aberrant expression on solid tumors. Thus, HA-1 might be an excellent target to boost the anti-solid tumor effect of allogeneic SCT without inducing severe GVHD. Here, we show that cytotoxic T lymphocytes (CTLs) solely targeting the human mHag HA-1 are capable of eradicating 3-dimensional human solid tumors in a highly mHag-specific manner in vitro, accompanied by interferon-gamma release. In vivo, HA-1-specific CTLs distribute systemically and prevent human breast cancer metastases in immunodeficient mice. Moreover, HA-1-specific CTLs infiltrate and inhibit the progression of fully established metastases. Our study provides the first proof for the efficacy of a clinically applicable concept to exploit single mismatched mHags with hematopoiesis- and solid tumor-restricted expression for boosting the anti-solid tumor effect of allogeneic SCT.
[Show abstract][Hide abstract] ABSTRACT: The primary lung bud originates from the foregut and develops into the bronchial tree by repetitive branching and outgrowing of the airway. The Sry related HMG box protein Sox2 is expressed in a cyclic manner during initiation and branching morphogenesis of the lung. It is highly expressed in non-branching regions and absent from branching regions, suggesting that downregulation of Sox2 is mandatory for airway epithelium to respond to branch inducing signals. Therefore, we developed transgenic mice that express a doxycycline inducible Sox2 in the airway epithelium. Continuous expression of Sox2 hampers the branching process resulting in a severe reduction of the number of airways. In addition, the bronchioli transiently go over into enlarged, alveolar-like airspaces, a pathology described as bronchiolization of alveoli. Furthermore, a substantial increase was observed of cGRP positive neuroendocrine cells and Delta Np63 isoform expressing (pre-) basal cells, which are both committed precursor-like cells. Thus, Sox2 prevents airways from branching and prematurely drives cells into committed progenitors, apparently rendering these committed progenitors unresponsive to branch inducing signals. However, Sox2 overexpression does not lead to a complete abrogation of the epithelial differentiation program.
[Show abstract][Hide abstract] ABSTRACT: ReGeneraTing Agents (RGTAs), a family of polymers engineered to protect and stabilize heparin-binding growth factors, have been shown to promote tissue repair and regeneration. In this study, the effects of one of these polymers, RGTA OTR4120, on healing of full-thickness excisional wounds in rats were investigated. Two 1.5 cm diameter circular full-thickness excisional wounds were created on the dorsum of a rat. After creation of the wounds, RGTA OTR4120 was applied. The progress of healing was assessed quantitatively by evaluating the wound closure rate, vasodilatory capability, and wound breaking strength. The results showed a triple increase of the local vascular response to heat provocation in the RGTA OTR4120-treated wounds as compared with vehicle-treated wounds. On days 14 and 79 after surgery, the wounds treated with RGTA OTR4120 gained skin strength 12% and 48% of the unwounded skin, respectively, and displayed a significantly increased gain in skin strength when compared with control animals. These results raise the possibility of efficacy of RGTA OTR4120 in accelerating surgically cutaneous wound healing by enhancing the wound breaking strength and improving the microcirculation.
Wound Repair and Regeneration 01/2008; 16(2):294-9. · 2.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues, the kidneys are the major dose-limiting organs, because of tubular reabsorption and retention of radioactivity. Preventing renal uptake or toxicity will allow for higher tumour radiation doses. We tested the cytoprotective drug amifostine, which selectively protects healthy tissue during chemo- and radiotherapy, for its renoprotective capacities after PRRT with high-dose [(177)Lu-DOTA(0),Tyr(3)]octreotate.
Male Lewis rats were injected with 278 or 555 MBq [(177)Lu-DOTA(0),Tyr(3)]octreotate to create renal damage and were followed up for 130 days. For renoprotection, rats received either amifostine or co-injection with lysine. Kidneys, blood and urine were collected for toxicity measurements. At 130 days after PRRT, a single-photon emission computed tomography (SPECT) scan was performed to quantify tubular uptake of (99m)Tc-dimercaptosuccinic acid (DMSA), a measure of tubular function.
Treatment with 555 MBq [(177)Lu-DOTA(0),Tyr(3)]octreotate resulted in body weight loss, elevated creatinine and proteinuria. Amifostine and lysine treatment significantly prevented this rise in creatinine and the level of proteinuria, but did not improve the histological damage. In contrast, after 278 MBq [(177)Lu-DOTA(0),Tyr(3)]octreotate, creatinine values were slightly, but not significantly, elevated compared with the control rats. Proteinuria and histological damage were different from controls and were significantly improved by amifostine treatment. Quantification of (99m)Tc-DMSA SPECT scintigrams at 130 days after [(177)Lu-DOTA(0),Tyr(3)]octreotate therapy correlated well with 1/creatinine (r(2)=0.772, p<0.001).
Amifostine and lysine effectively decreased functional renal damage caused by high-dose [(177)Lu-DOTA(0),Tyr(3)]octreotate. Besides lysine, amifostine might be used in clinical PRRT as well as to maximise anti-tumour efficacy.
European journal of nuclear medicine and molecular imaging 05/2007; 34(5):763-71. · 5.11 Impact Factor