2010
DOI: 10.1016/j.bcp.2009.12.022
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The alkylating prodrug J1 can be activated by aminopeptidase N, leading to a possible target directed release of melphalan

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Cited by 53 publications
(74 citation statements)
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“…Mel-flufen is rapidly incorporated into the tumor cells, followed by intracellular hydrolysis, which in part is mediated by aminopeptidase N (ANPEP), an enzyme overexpressed in several tumor cell malignancies (18). Studies using solid tumor cell models showed that treatment with mel-flufen causes at least a 10-fold higher loading of melphalan, which explain its higher tumor cell cytotoxicity (15)(16)(17)19). To date, the mel-flufen activity against multiple myeloma cells is undefined.…”
Section: Introductionmentioning
confidence: 99%
“…Mel-flufen is rapidly incorporated into the tumor cells, followed by intracellular hydrolysis, which in part is mediated by aminopeptidase N (ANPEP), an enzyme overexpressed in several tumor cell malignancies (18). Studies using solid tumor cell models showed that treatment with mel-flufen causes at least a 10-fold higher loading of melphalan, which explain its higher tumor cell cytotoxicity (15)(16)(17)19). To date, the mel-flufen activity against multiple myeloma cells is undefined.…”
Section: Introductionmentioning
confidence: 99%
“…Mel‐flufen biotransformation and cell killing effects has in other tumour types been shown to depend on aminopeptidases (Chauhan et al., 2013; Wickstrom et al., 2010). The effect of bestatin‐mediated aminopeptidase blockade on mel‐flufen effects in UC was therefore evaluated (Figure 6A).…”
Section: Resultsmentioning
confidence: 99%
“…One may speculate that the intact mel‐flufen or the de‐esterified form of mel‐flufen could possibly function as a reservoir of mel‐flufen which gradually can be converted to the active melphalan and contribute to the observed increased cytotoxicity after mel‐flufen exposure in these cells. The conversion of mel‐flufen to melphalan has in other solid tumour cells been shown to rely on aminopeptidases, which are inhibited by bestatin (Chauhan et al., 2013; Wickstrom et al., 2010). Also in UC cells, we found evidence of aminopeptidases to be critically involved as bestatin blocked intracellular melphalan accumulation after mel‐flufen treatment and, accordingly, reduced mel‐flufen‐induced cell death.…”
Section: Discussionmentioning
confidence: 99%
“…Under the action of aminopeptidases, like aminopeptidase N [4], melflufen is hydrolyzed, leading to high intracellular concentrations of alkylating moieties (e.g. melphalan), able to interact with nucleic acids within the tumor cells [5].…”
Section: Introductionmentioning
confidence: 99%
“…In AML, APN is and is expressed on stem cells and leukemic blasts [6, 10], on the cell surface [11, 12] and in the cytoplasm [12], and recently occurrence of APN was also demonstrated in microvesicles from patients with myeloid tumors [13]. Since APN mediates cleavage of melflufen to its parental drug melphalan in the tumor cell cytoplasm, or in environment with high concentration of APN, a clinical usability of melflufen in AML is suggested [4]. …”
Section: Introductionmentioning
confidence: 99%