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

@article{Gullbo2004AntitumorEA,
  title={Antitumor efficacy and acute toxicity of the novel dipeptide melphalanyl-p-L-fluorophenylalanine ethyl ester (J1) in vivo},
  author={J. Gullbo and E. Lindhagen and S. Bashir-Hassan and Marcus Tullberg and H. Ehrsson and R. Lewensohn and P. Nygren and M. de la Torre and K. Luthman and R. Larsson},
  journal={Investigational New Drugs},
  year={2004},
  volume={22},
  pages={411-420}
}
The novel alkylating dipeptide melphalanyl-p-L-fluorophenylalanine ethyl ester (J1) was evaluated for acute toxicity and antitumor activity in mice, with melphalan as a reference. To determine a safe and tolerable dose for efficacy studies the acute toxicity following intravenous injection in the tail vein was monitored using a 14-day schedule with up to four doses. The highest tested dose, 25 μmoles/kg, was considered close to this level, with minor effects on body weight gain but significant… Expand
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References

SHOWING 1-10 OF 24 REFERENCES
High anticancer efficacy of L-proline-m-bis (2-chloroethyl) amino-L-phenylalanyl-L-norvaline ethyl ester hydrochloride (MF13) in vivo.
TLDR
MF13 showed a therapeutic effect in liquid tumors and induced complete remission even in late stage malignancies, and activity of MF13 in murine hepatoma in vivo was stronger than its precursor m-sarcolysin. 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
Antitumor activity of the novel melphalan containing tripeptide J3 (L-prolyl-L-melphalanyl-p-L-fluorophenylalanine ethyl ester): comparison with its m-L-sarcolysin analogue P2.
Peptichemio (PTC), a mixture of six oligopeptides all containing m-L-sarcolysin, has previously shown impressive results in clinical trials. The tripeptide P2Expand
Structure-activity relationship for alkylating dipeptide nitrogen mustard derivatives.
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. 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
Comparison of the cytotoxic activity of melphalan with L-prolyl-m-L-sarcolysyl-L-p-fluorophenylalanine in human tumour cell lines and primary cultures of tumour cells from patients.
TLDR
The results show that P2 is the most potent component of PTC and demonstrates a favourable activity profile compared with Mel, and suggest that further investigation of P2 as a potential anti-tumour agent is warranted. Expand
Multiple transport pathways for L1210 cells: uptake of PTT.119, a bifunctional alkylator with carrier amino acids.
TLDR
PTT.119 entry into leukemia cells was examined using competition transport assays assessing the ability of the tripeptide to compete with various amino acids and nonmetabolizable substrates for carrier receptors of the L, A and ASC transport systems and indicates that L121 cells actively transport PTT.119 primarily by the BCH-sensitive, AIB- sensitive, MeAIB-insensitive L carrier system. Expand
Determination of drug effect on tumour cells, host animal toxicity and drug pharmacokinetics in a hollow-fibre model in rats
TLDR
This study illustrates the possibility of measuring antitumour effect, haematological toxicity and pharmacokinetics in the same animal using the hollow-fibre model. Expand
High-dose topotecan, melphalan, and cyclophosphamide (TMC) with stem cell support: a new regimen for the treatment of advanced ovarian cancer.
TLDR
With a topotecan dose of 4.0 mg/m(2)/day x 5 days, the TMC regimen has acceptable toxicity and produces high response rates, and TMC should be considered a potential regimen for future randomized trials in patients with advanced ovarian cancer. Expand
Carrier-mediated transport of oligopeptides in the human fibrosarcoma cell line HT1080.
TLDR
This is the first report showing that a dipeptide transport system, which is similar but not identical to the well-characterized oligopeptide transporters PepT1 and PepT2, exists in fibroblast-derived tumor cells but not in normal fibroblasts. Expand
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