Targeted radionuclide therapy using radioiodinated compounds with a specific affinity for melanoma tissue is a promising treatment for disseminated melanoma, but the candidate with the ideal kinetic profile remains to be discovered. Targeted radionuclide therapy concentrates the effects on tumor cells, thereby increasing the efficacy and decreasing the morbidity of radiotherapy. In this context, analogues of N-(2-diethylaminoethyl)-4-iodobenzamide (BZA) are of interest. Various (hetero)aromatic analogues 5 of BZA were synthesized and radioiodinated with (125)I, and their biodistribution in melanoma-bearing mice was studied after i.v. administration. Most [ (125)I] 5-labeled compounds appeared to bind specifically and with moderate-to-high affinity to melanoma tumor. Two compounds, 5h and 5k, stood out with high specific and long-lasting uptake in the tumor, with a 7- and 16-fold higher value than BZA at 72 h, respectively, and kinetic profiles that makes them promising agents for internal targeted radionuclide therapy of melanoma.
Melanoma is a neoplasia of dramatically increasing incidence that has a propensity to spread rapidly. Early detection is fundamental and patient management requires reliable, sensitive and reproducible staging methods, such as a single examination by planar scintigraphy or single-photon emission tomography (SPET) using a radiopharmaceutical with selectivity for melanoma tissue. Among iodobenzamides reported to possess an affinity for melanoma, a new compound, N-(2-diethylaminoethyl)-2-iodobenzamide (BZA(2)), was selected for a clinical trial in view of its pharmacokinetic experimental profile in melanoma-bearing mice. Planar whole-body scintigraphy using (123)I-BZA(2) was performed in 25 patients with histologically proven cutaneous melanoma. Performance was evaluated in two groups of patients with one or more documented secondary lesions ( n=13) or with no known secondary lesions ( n=12), and results were compared with those of conventional investigation techniques. No adverse clinical or biological events were recorded. Lesions were imaged by increased tracer uptake, and good quality images were obtained 4 h after administration. After a follow-up of more than 1 year, the overall results of (123)I-BZA(2) scintigraphy on a per patient basis showed a sensitivity of 100%, a specificity of 95%, a positive predictive value of 86% and a negative predictive value of 100%. The proven secondary lesions were imaged with a sensitivity of 100% and a specificity of 91%. In seven patients with suspected metastases, the absence of (123)I-BZA(2) uptake was confirmed as true negative, and in one patient without suspected metastases, (123)I-BZA(2) scintigraphy revealed a gastric lesion. Hence eight diagnoses would have been modified by (123)I-BZA(2) scintigraphy data. (123)I-BZA(2) allowed discrimination between benign and malignant lesions and, in the case of malignancies, between those of melanomatous origin and others. This compound, which is selective for melanoma tissue, appears promising for the staging and restaging of melanoma.
The ability to follow phospholipid (Plp) metabolism is of paramount importance in many circumstances in which cell survival and cell proliferation are of concern-for example in neurological disorders and cancer (1,2). NMR spectroscopy has long been known to be important tool for exploring Plp metabolism (3-6). Novel NMR developments, such as high-resolution magic angle spinning (HRMAS) probes, have provided improved spectra of cultured cells (7) and normal (8,9) and cancer (10 -12) tissues. Recently, using HRMAS together with proton total correlation spectroscopy (TOCSY), we showed that a mousebearing B16 melanoma tumor responded to chloroethyl nitrosourea (CENU) treatment in vivo by altering its Plp metabolism (12).The first purpose of the present study was to demonstrate on cultured B16 melanoma cells in vitro that HRMAS proton TOCSY cross-peak signal variations of Plp derivatives reflected concentration variations. The second purpose was to determine the Plp metabolism response of cultured B16 melanoma cells to CENU treatment in vitro, as a model for Plp metabolism alterations previously observed in vivo.The Plp derivatives that were simultaneously observed using proton TOCSY were choline (Cho), phosphocholine (PC), cytidyl-diphosphate-choline (CDP-Cho), ethanolamine (Eth), phosphoethanolamine (PE), CDP-ethanolamine (CDP-Eth) (all of which are derivatives of the phosphatidylcholine (PtdCho) and phosphatidylethanolamine (PtdEth) biosynthetic pathways), and glycerophosphocholine (GPC) and glycerophosphoethanolamine (GPE) (derivatives of PtdCho and PtdEth hydrolysis) (1-3).As regards the most expressed Plp derivatives in cultured B16 melanoma cells, HRMAS proton TOCSY signals revealed linearity with 1D saturation recovery signals, the NMR spectroscopy reference for quantifying concentrations. Therefore, HRMAS proton TOCSY was used to quantify concentration changes of water-soluble Plp derivatives in CENU-treated cultured melanoma cells. The response of cultured B16 melanoma cells to CENU treatment involved a transient accumulation of GPC and GPE, a down-regulation of PC and increase of CDP-Eth during cell proliferation inhibition, and a dramatic and irreversible rise of PE during and after cell proliferation inhibition. These data are discussed in relation to mouse-bearing B16 melanoma tumor response to CENU in vivo, and to Plp metabolism enzymatic involvement. METHODS ChemicalsNЈ-[2-chloroethyl]-N[2-(methylsulfonyl)ethyl]-NЈ-nitrosourea (cystemustine) is a CENU antineoplastic agent (13) that has been proposed for the treatment of human malignant melanoma and glioma. Cystemustine (Orphachem, Clermont-Ferrand, France) was supplied as a 5-mM solution in 0.9% NaCl. D 2 O (SDS, Peypin, France) was used to lock the spectrometer. Cell CulturesTransplantable B16 melanoma cells originating from C57BL6/6J Ico mice (ICIG, Villejuif, France) were adapted
The development of alternative therapies for melanoma treatment is of great interest as long-term tumour regression is not achieved with new targeted chemotherapies on selected patients. We previously demonstrated that radioiodinated heteroarylcarboxamide ([ 131 I]ICF01012) induced a strong anti-tumoural effect by inhibiting both primary tumour growth and dissemination process in a B16BL6 melanoma model. In our study, we show that a single injection of [ 131 I]ICF01012 (ranging from 14.8 to 22.2 MBq) was effective and associated with low and transient haematological toxicity. Concerning pigmented organs, cutaneous melanocytes and skin were undamaged. In 30% of treated animals, no histological alteration of retina was observed, and in the remaining 70%, damages were restricted to the optic nerve area. Using the Medical Internal Radiation Dose methodology, we determined that the absorbed dose in major organs is very low (<4 Gy) and that a delivery of 30 Gy to the tumour is sufficient for an effective anti-tumoural response. Molecular analyses of treated tumours showed a strong radiobiological effect with a decrease in proliferation, survival and pro-angiogenic-related markers and an increase in tumour suppressor gene expression, melanogenesis and anti-angiogenic markers. All these features are in accordance with a tumour cell death mechanism that mainly occurs by mitotic catastrophe and provide a better understanding of in vivo anti-tumoural effects of Metastatic melanoma has a poor prognosis with an estimated death rate ranging from 1.8 to 3.5 per 100,000 cases worldwide. 1,2 As with other cancers, chemotherapy (dacarbazine) remained the conventional treatment with poor benefit for over half a century. Two strategies have improved melanoma treatment, one using the tumour immune response by blocking cytotoxic T-lymphocyte activation (antibody anti-CTL4) 3 and the other targeting BRAF. 4 A recent multicentre phase 1 clinical trial testing a mutated BRAF (V600E) inhibitor showed complete or partial tumour regression in the majority of patients. 5 However, BRAF mutations are detected in only 60% of melanoma cases, and the therapy involves selection of patients with tumours that carry the V600E BRAF mutation. 5,6 Furthermore, most treated patients acquire resistance to this inhibitor after initial clinical response. 7 Metastatic melanoma is always described as a refractory disease, and new observations suggest that combined therapies will have a greater impact on melanoma residual activity. As the mechanisms of resistance to treatment rely on tumour adaptation by somatic mutations, 8 other non-protein targets such as melanin could be considered for future therapies.Melanin pigment is detected in more than 90% of primary melanoma cases, and thus, a strategy targeting this pigment
In recent years, there has been dramatic worldwide increase in incidence of malignant melanoma. Although localised disease is often curable by surgical excision, metastatic melanoma is inherently resistant to most treatments. In this context, targeted radionuclide therapy could be an efficient alternative. After pharmacomodulation study, we selected a quinoxaline derivative molecule (ICF01012) for its high, specific and long-lasting uptake in melanoma with rapid clearance from nontarget organs providing suitable dosimetry parameters for targeted radiotherapy. Aim of this study was to investigate, in vivo, efficacy of [ 131 I]ICF01012 on nonmetastatic B16F0, metastatic B16Bl6 or human M4Beu melanoma tumours. First, colocalisation of ICF01012 with melanin by SIMS imaging was observed. Second, we showed that treatment drastically inhibited growth of B16F0, B16Bl6 and M4beu tumours whereas [ 131 I]NaI or unlabelled ICF01012 treatment was without significant effect. Histological analysis and measure of PCNA proliferation marker expression showed that residual B16 tumour cells exhibit a significant loss of aggressiveness after treatment. This effect is associated with a lengthening of the treated-mice survival time. Moreover, with B16Bl6 model, 55% of the untreated mice had lung metastases whereas no metastasis was counted on treated group. Our data demonstrated a strong anti-tumoural effect of [ 131 I]ICF01012 for radionuclide therapy on murine and human in vivo pigmented melanoma models, whatever their dissemination profiles and their melanin content be. Further studies will attempt to optimise therapy protocol by increasing the balance between the anti-tumoural effect and the safety on nontarget organs. ' 2009 UICC
We have shown that -tubulin was alkylated by a microtubule disrupter, urea (ICEU), on a glutamic acid residue at position 198 and not on the previously proposed reactive cysteine 239. ICEU belongs to the 4-substituted-phenyl-NЈ-(2-chloroethyl) urea class that alkylates mainly cellular proteins. Previous studies have shown that the tertbutyl (tBCEU) and iodo (ICEU) derivatives induce microtubule disruption because of -tubulin alkylation. tBCEU was supposed to bind covalently to cysteine 239 of -tubulin, but this binding site was not clearly confirmed (Cancer Res 60:985-992, 2000). We have isolated and analyzed -tubulin after twodimensional gel electrophoresis of proteins from B16 cells incubated with ICEU. Alkylated -tubulin had a lower apparent molecular weight and a more basic isoelectric point than the unmodified protein. 125 I]CEU was effectively bound to the modified -tubulin but using matrix-assisted laser desorption ionization/time-of-flight mass spectrometry, we demonstrated that none of the cysteine residues of -tubulin was linked to the alkylating agent. In contrast, peptide masses at m/z 4883 and 1792 in trypsin or Asp-N digestions of -tubulin confirmed binding of iodophenylethylureido moiety to peptides or [197][198][199][200][201][202][203][204][205][206][207][208] respectively. Fragmentation analyses by electrospray mass spectrometry using triply charged ions of peptide identified a glutamic acid at position 198 as target for alkylation via an ester bond with ICEU. This amino acid located in the intermediate domain of the -tubulin should play an essential role in the conformational structure necessary for the interaction between dimers in the protofilament.
Metastatic melanoma is one of the most aggressive forms of skin cancer and has a poor prognosis. We have previously identified Annexin A1 (ANXA1) as a potential murine melanoma-spreading factor that may modulate cell invasion by binding to formyl peptide receptors (FPRs). Here, we report that (1) in a B16Bl6 spontaneous metastasis model, a siRNA-induced decrease in tumoral ANXA1 expression significantly reduced tumoral MMP2 activity and number of lung metastases; (2) in a retrospective study of 61 patients, metastasis-free survival was inversely related to ANXA1 expression levels in primary tumors (HR 3.15 [1.03-9.69], p = 0.045); (3) in human melanoma cell lines, ANXA1 level was positively correlated with in vitro invasion capacity whereas normal melanocytes contained low ANXA1 levels, and (4) the ANXA1 N-terminal peptide ANXA12-26 stimulated MMP2 activity after interaction with FPRs and significantly stimulated the in vitro invasion of melanomas by acting on FPRs. These findings identify ANXA1 as a proinvasive protein in melanoma that holds promise as a potential prognostic marker and therapeutic target.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.