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

@article{Gullbo2003AntitumorAO,
  title={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},
  author={Joachim Gullbo and Sumeer Dhar and Kristina Luthman and Hans Ehrsson and Rolf Lewensohn and Peter Nygren and Rolf Larsson},
  journal={Anti-Cancer Drugs},
  year={2003},
  volume={14},
  pages={617-624}
}
Peptichemio, a mixture of six short oligopeptides all comprising the alkylating amino acid m-L-sarcolysin, has shown clinical activity in several malignancies. Previous studies have suggested that activity mainly resides in one of the peptides, P2 (L-prolyl-m-L-sarcolysyl-p-L-fluorophenylalanine ethyl ester). 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… 

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 P2

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.

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.

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.

Melflufen - a peptidase-potentiated alkylating agent in clinical trials.

TLDR
It is hypothesized that melflufen could provide better efficacy but no more toxicity than what is achieved with melphalan, an assumption so far supported by experiences from hollow fiber and xenograft studies in rodents as well as by clinical data from patients with solid tumors and multiple myeloma.

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

TLDR
The ex vivo profile of J 1 suggests that further evaluation of J1 as the alkylating agent in for example aggressive breast cancer might be of particular interest, preferentially in combination with DNA-topoisomerase II inhibitors like etoposide.

In vitro and in vivo activity of melflufen (J1)in lymphoma

TLDR
This study confirms previous reports of a targeting related potency superiority of melflufen compared to that of melphalan and appears to be a candidate for further evaluation in the treatment of this group of malignant diseases.

In vitro and in vivo activity of melflufen ( J 1 ) in lymphoma

TLDR
This study confirms previous reports of a targeting related potency superiority of melflufen compared to that of melphalan and appears to be a candidate for further evaluation in the treatment of this group of malignant diseases.

References

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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.

Increased toxicity and DNA cross-linking by peptide bound m-L-sarcolysin (Peptichemio) as compared to melphalan and m-L-sarcolysin in human melanoma cell lines.

TLDR
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TLDR
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.

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TLDR
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TLDR
l-mSL plays an important role in the mechanism of action of PTC, and the stability of some of the peptides was drastically decreased in blood, the degradation half-lives being only about 1 min.

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TLDR
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TLDR
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TLDR
Through these reactions, DNA synthesis and ribonuclease are inhibited and cross-linking of DNA strands and protein develops, in­ activating the functions of DNA and causing mutations and chromosome aber­ rations.

Peptichemio versus melphalan (L‐PAM) in advanced breast cancer

TLDR
It is concluded that peptichemio is an active agent in advanced breast cancer, but L‐PAM is ineffective in previously treated patients with metastatic breast cancer.

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TLDR
According to these results, the PVP protocol would appear susceptible of offering a major contribution to the chemotherapy of diffuse NHL.