Activity of Hydrolytic Enzymes in Tumour Cells is a Determinant for Anti-tumour Efficacy of the Melphalan Containing Prodrug J1

@article{Gullbo2003ActivityOH,
  title={Activity of Hydrolytic Enzymes in Tumour Cells is a Determinant for Anti-tumour Efficacy of the Melphalan Containing Prodrug J1},
  author={Joachim Gullbo and Malin Wickstr{\"o}m and Marcus Tullberg and Hans Ehrsson and Rolf Lewensohn and Peter Nygren and Kristina Luthman and Rolf Larsson},
  journal={Journal of Drug Targeting},
  year={2003},
  volume={11},
  pages={355 - 363}
}
Recently, we presented a series of melphalan containing di- and tripeptides with high cytotoxic activity and J1 (l-melphalanyl-p-l-fluorophenylalanine ethyl ester) was identified as one of the most interesting compounds. It was speculated that the increased activity compared to melphalan itself, demonstrated both in vitro and in vivo, resided in increased transport over the tumour cell membrane and/or hydrolytic cleavage and liberation of melphalan inside the cells. Indeed, overexpression of… 

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References

SHOWING 1-10 OF 27 REFERENCES

Structure-activity relationship for alkylating dipeptide nitrogen mustard derivatives.

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 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

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.

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.

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.

Plasmin-activated prodrugs for cancer chemotherapy. 2. Synthesis and biological activity of peptidyl derivatives of doxorubicin.

We have synthesized peptidyl prodrugs of doxorubicin (Dox) designed to be selective substrates of plasmin. Such prodrugs might be locally activated by the elevated levels of plasmin produced near

Derivatives of melphalan designed to enhance drug accumulation in cancer cells.

The results suggest that the cellular uptake of the dipeptide derivatives of melphalan and their esters is probably more facilitated via passive diffusion than being facilitated/being facilitated by the overall neutralisation of these amino acids and dipepeptides.

Bestatin as an experimental tool in mammals.

Aminopeptidase N emerges as the major target for the effects of bestatin on the immune system and some of its effects on tumor growth and the endometrium, and bestatin-sensitive LTA4 hydrolase generates the potent chemotactic agent, LTB4.

Enzymatic activation of a doxorubicin-peptide prodrug by prostate-specific antigen.

An inactive prodrug was synthesized by coupling the primary amine of doxorubicin to the COOH-terminal carboxyl of a seven-amino acid peptide carrier to liberate the active cytotoxin L-leucyl-doxorUBicin in vitro.

Protease-mediated fragmentation of p-amidobenzyl ethers: a new strategy for the activation of anticancer prodrugs.

A new anticancer prodrug activation strategy based on the 1,6-elimination reaction of p-aminobenzyl ethers is described, which extends the use of the self-immolative p-amines group for the fragmentation of aromatic ethers and provides a new strategy for antic cancer prodrug development.

Amino acid and dipeptide derivatives of daunorubicin. 2. Cellular pharmacology and antitumor activity on L1210 leukemic cells in vitro and in vivo.

Intracellular DNR was found when the L1210 cells were incubated in the presence of DNR, Leu-Leu-DNR, leu-Ala-D NR, Lee-Lei-DNH, and Leu/Ala/DNR and all the derivatives are less active than DNR.

Protease-activated "prodrugs" for cancer chemotherapy.

The greater selectivity of action of the peptidylProdrugs against transformed cell cultures suggests that these or similar prodrugs that are substrates for tumor-associated proteases may show increased therapeutic effectiveness in the treatment of tumors that produce sufficiently increased amounts of plasminogen activator.