The novel alkylating prodrug J1: diagnosis directed activity profile ex vivo and combination analyses in vitro

@article{Wickstrm2007TheNA,
  title={The novel alkylating prodrug J1: diagnosis directed activity profile ex vivo and combination analyses in vitro},
  author={M. Wickstr{\"o}m and C. Haglund and H. Lindman and P. Nygren and R. Larsson and J. Gullbo},
  journal={Investigational New Drugs},
  year={2007},
  volume={26},
  pages={195-204}
}
SummaryObjective: The dipeptide J1 acts as a prodrug of melphalan with a significant increased potency in vitro resulting from activation by cellular aminopeptidases. The current study was performed to evaluate the ex vivo profile of J1 using 176 primary tumor cell cultures from patients. In addition, the activity of J1 in combination with eight standard drugs, representing different mechanistic classes, was studied in nine different human tumor cell lines of different histopathological origin… Expand
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The novel melphalan prodrug J1 inhibits neuroblastoma growth in vitro and in vivo
TLDR
The melphalan prodrug J1 is highly active in models of neuroblastoma in vitro and in vivo, encouraging further clinical development in this patient group. Expand
Activity of Hydrolytic Enzymes in Tumour Cells is a Determinant for Anti-tumour Efficacy of the Melphalan Containing Prodrug J1
TLDR
The results show that the activity of the dipeptide mustards is highly dependent on intracellular hydrolysis, which result in rapid intrACEllular release of the alkylating unit in cells with high enzymatic activity. Expand
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The results indicate that the activity of these compounds not only relies on their chemical reactivity, but also on active biological interactions such as transport across membranes and/or enzymatic liberation of reactive molecular entities. Expand
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TLDR
The results indicate that the promising in vitro data from the previous studies of J1 seems translatable into the in vivo situation, and at equal doses of alkylating units J1 was more active in the mouse hollow-fiber model, but showed similar general toxicity. Expand
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TPT cytotoxicity appears to be enhanced more by combination with certain DNA-damaging agents than by combination in combination with antimetabolites or antimicrotubule agents. Expand
Antitumor activity of the alkylating oligopeptides J1 (L-melphalanyl-p-L-fluorophenylalanine ethyl ester) and P2 (L-prolyl-m-L-sarcolysyl-p-L-fluorophenylalanine ethyl ester): comparison with melphalan
TLDR
In the present study the in vitro activity of P2 was further investigated and compared to melphalan and the novel alkylating dipeptide J1 (L-melphalanyl-p-L-fluorophenylalanine ethyl ester), which is structurally related to P2 andmelphalan. Expand
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The results indicate that the relative activity of cytotoxic drugs in different diagnoses may be detected by the FMCA, and 'phase II trials ex vivo' using non-clonogenic cytotoxicity assays might be used to make clinical trials more effective by targeting trials to diagnoses in which a new agent is most likely to be active. Expand
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Screening of mechanistically annotated compounds on drug-resistant cancer cells can identify compounds with selective activity and provide a basis for the development of novel treatments of drug- resistant malignancies. Expand
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Cell lines resistant to five antitumor alkylating agents (CDDP, PAM, 4-HC, HN2, and BCNU) were developed from five parental human tumor lines representative of solid tumors with a range ofExpand
Clinical Significance of Aminopeptidase N in Non–Small Cell Lung Cancer
TLDR
The data suggest the expression of APN/CD13 for patients with NSCLC to be associated with a poor prognosis and angiogenesis, and the inhibition of APn/ CD13 may be an effective new molecular target therapy for patientsWith NSCLc. Expand
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