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={Malin Wickstr{\"o}m and Caroline Anderberg Haglund and Henrik Lindman and Peter Nygren and Rolf Larsson and Joachim 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… 

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References

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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.

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.

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TLDR
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.

Antitumor efficacy and acute toxicity of the novel dipeptide melphalanyl-p-L-fluorophenylalanine ethyl ester (J1) in vivo

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.

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TLDR
TPT cytotoxicity appears to be enhanced more by combination with certain DNA-damaging agents than by combination in combination with antimetabolites or antimicrotubule agents.

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.

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TLDR
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.

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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.

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TLDR
The derived ex vivo therapeutic index could enhance choice of chemotherapy by reducing toxicity and/or improving efficacy, and individual patient therapeutic index varied markedly for different drugs, ranging from extremely unfavourable through excellent reflecting patient heterogeneity.