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

  title={Antitumor efficacy and acute toxicity of the novel dipeptide melphalanyl-p-L-fluorophenylalanine ethyl ester (J1) in vivo},
  author={Joachim Gullbo and Elin Lindhagen and Saadia Bashir-Hassan and Marcus Tullberg and Hans Ehrsson and Rolf Lewensohn and Peter Nygren and Manuel de la Torre and Kristina Luthman and Rolf Larsson},
  journal={Investigational New Drugs},
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… 

The novel melphalan prodrug J1 inhibits neuroblastoma growth in vitro and in vivo

The melphalan prodrug J1 is highly active in models of neuroblastoma in vitro and in vivo, encouraging further clinical development in this patient group.

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

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 Antitumor Activity of a Novel Alkylating Agent, Melphalan-Flufenamide, against Multiple Myeloma Cells

The preclinical study supports clinical evaluation of mel-flufen to enhance therapeutic potential of melphalan, overcome drug-resistance, and improve multiple myeloma patient outcome.

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

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

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 anti-leukemic activity of the peptidase-potentiated alkylator melflufen in acute myeloid leukemia

Melflufen demonstrates high and significant preclinical activity in AML and further clinical evaluation seem warranted in this disease, as well as in a patient derived xenograft study.

A novel transport and delivery mechanism underpins the effectiveness of prolyl‐m‐sarcolysyl‐p‐fluorophenylalanine (PSF) in a human melanoma xenograft nude‐mouse model

In melanoma‐bearing nude mice, escalating doses of PSF showed dose‐dependent responses and reached tumor regression with an optimal dose of 20 mg/kg for 1 month, and a comparison of PS F with its free moiety m‐sarcolysin and melphalan showed a highly significant advantage.

First-in-human, phase I/IIa clinical study of the peptidase potentiated alkylator melflufen administered every three weeks to patients with advanced solid tumor malignancies

Melflufen can safely be given to cancer patients, and the toxicity profile was as expected for alkylating agents; RPTD is 50 mg Q3W.



High anticancer efficacy of L-proline-m-bis (2-chloroethyl) amino-L-phenylalanyl-L-norvaline ethyl ester hydrochloride (MF13) in vivo.

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.

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.

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

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.

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

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.

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.

Multiple transport pathways for L1210 cells: uptake of PTT.119, a bifunctional alkylator with carrier amino acids.

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.

Determination of drug effect on tumour cells, host animal toxicity and drug pharmacokinetics in a hollow-fibre model in rats

This study illustrates the possibility of measuring antitumour effect, haematological toxicity and pharmacokinetics in the same animal using the hollow-fibre model.

High-dose topotecan, melphalan, and cyclophosphamide (TMC) with stem cell support: a new regimen for the treatment of advanced ovarian cancer.

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.

Carrier-mediated transport of oligopeptides in the human fibrosarcoma cell line HT1080.

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.