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The prodrug J1 is activated by aminopeptidase N, which results in high intracellular melphalan concentrations, DNA damage and apoptosis
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
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URN: urn:nbn:se:uu:diva-96364OAI: oai:DiVA.org:uu-96364DiVA: diva2:170915
Available from: 2007-11-09 Created: 2007-11-09 Last updated: 2010-01-13Bibliographically approved
In thesis
1. Preclinical Studies of the Melphalan Prodrug J1 for Cancer Therapy
Open this publication in new window or tab >>Preclinical Studies of the Melphalan Prodrug J1 for Cancer Therapy
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

J1 (L-melphalanyl-L-p-fluorophenylalanyl ethyl ester) is a dipeptide derivative of the alkylating agent melphalan with increased cytotoxicity. In this thesis the preclinical pharmacology of J1 has been characterized.

Our results show that J1 rapidly enters the cells, where melphalan is released by hydrolysis. The maximum concentration (Cmax) of melphalan was detected 15 min after exposure to J1 in human cancer cell lines. In comparison, melphalan exposure resulted in a 10-fold lower Cmax that was shifted to later time points. J1 induced more DNA damage and apoptosis than melphalan. The cytotoxic activity and release of melphalan from J1 were inhibited by preincubating cells with the aminopeptidase inhibitor bestatin. In accordance with these results, we showed that J1 is a substrate for aminopeptidase N (APN), which may result in increased tumor selectivity.

J1 effectively inhibited cell growth in a set of neuroblastoma cell lines. Athymic mice carrying neuroblastoma xenografts were treated either with equimolar doses of melphalan or J1. J1 inhibited the tumor growth more effectively than melphalan and the untreated control, and was associated with higher caspase-3 activation, fewer proliferating tumor cells and decreased mean vascular density.

J1 and melphalan showed similar activity profiles when tested in 176 primary tumor cell cultures from patients, but J1 exhibited 50- to 100-fold higher potency. The difference was greater in some diagnoses (e.g. breast cancer, NHL and AML), and was exceptionally large in some breast cancer samples with aggressive phenotypes. A combination screening of J1 and standard chemotherapeutics yielded mostly additive interactions, except for etoposide which induced synergy in all tested cell lines.

In conclusion, the melphalan prodrug J1 is effectively transported into the cells, where aminopeptidases (for example APN) catalyze the formation of melphalan. J1 shows promising preclinical potential in the diagnoses neuroblastoma and breast cancer.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 59 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 285
Pharmacology, Pharmacology, Chemotherapy, Melphalan prodrug, Cancer, Farmakologi
urn:nbn:se:uu:diva-8285 (URN)978-91-554-7005-0 (ISBN)
Public defence
2007-11-30, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15
Available from: 2007-11-09 Created: 2007-11-09Bibliographically approved

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