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

Abstract

Summary m-L-sarcolysin (m-L-SL) is an isomer of melphalan (Mel) with the di(2-chloroethyl) amino group being substituted in the meta position of phenylalanine. By covalent conjugation of amino acids to m-L-SL. a peptide complex consisting of six m-L-SL-based oligopeptides known as peptichemio (PTC) was developed previously. In the present study, the cytotoxic activity pattem of the different oligopeptides of PTC was investigated in ten human tumour cell lines representing different mechanisms of cytotoxic drug resistance using the fluorometric microcufture cytotoxicity assay (FMCA). In the cell line panel, Keywords: melphalan: L-prolyl-m-L-sarcolysyl-L-p-fluorophenylalanine; cytotoxicity assay; human tumour cell: drug resistance m-L-sarcolx sin ( m-L-SL ) is an isomer of melphalan ( Mel) wxith the di( 2-chloroethv1) amino group being substituted in the meta position of phenx lalanine. Bv cox-alent conju2ation of different aniino acids at the amino and carboxxl groups of m-L-SL. a peptide complex including six oligopeptides knoxx-n as peptichemio (PTC) \vas svnthesized prexiouslx (De Barbieri. 1972). The main rationale for svnthesizing, PFC wias that of creatin2 a substance that is simultaneouslx endowed w-ith cxtotoxic actix-itv because of the alkx lating group and a selecti-xe uptake in neoplastic cells (De Barbieri. 1972). In sexeral clinical inxestigations. PTC has showin actix itx in a Aiide spectrum of human malignancies (Hug et al. 1980: Paccagnella et al. 1985). In the clinic PTC has showin acti-it-in human multiple myeloma resistant to treatment wxith alkvlating agents IPaccagnella et al. : Zaniboni et al. 1988. Increased cx-totoxicitx-exerted by PTC as compared w-ith Mel and m-L-SL has been showin on tumour cell lines (Lewxensohn et al. 1991a). One of the alkylating peptides in PTC is L-prolyl-m-Lsarcol\s -l-L-p-fluorophenx lalamnne (P21. We haxe previously found that P2 is sex-eral-fold more toxic to human melanoma cells than m-L-SL alone w-hen tested bv a clono2enic assav (Hansson et al. 19911. Increased levels of DNA cross-link-in2 w-ere noted after MATERIALS AND METHODS Cell linesTo evaluate the actixvitv patterns of P2 and M,el a human cell line panel of four sensitixve parental cell lines. fi e drug resistant sublines. representing different mechanisms of resistance. and one cell line w-ith primary resistance wxas used. The cell lines included x ere the mveloma cell line RPMII 8226/S and its sublines 8226/Dox; and 8226/LR-5 (kind gifts from W'S Dalton.

Tinker, Tailor, Soldier, Spy: The Diverse Roles That Fluorine Can Play within Amino Acid Side Chains

“…A major limitation of compound 58 is its inability to traverse cell membranes. This limitation can be overcome through a prodrug approach, in which mephalan is temporarily masked as a di-or a tripeptide (e.g., 59-60, Figure 4) [194,195]. The presence of the fluorinated amino acid in 59-60 enhances the drugs' membrane permeability, and thereby substantially boosts the anticancer potency in each case.…”

Postgenomic chemistry: New problems and challenges

“…These are: (1) A potential possibility of the unnatural amino acid incorporation into proteins infinitely widens the spectrum of the novel proteins to be synthesized. The elaboration of the effective methods to synthesize the proteins and enzymes containing element-organic amino acid analogs gives us hope to obtain the proteins and enzymes with the properties previously unknown; (2) Novel classes of anticancer and antiviral agents could be proposed using the amino acid analogs and their derivatives [54,55]; (3) The replacement of any amino acid significant part by their synthetic analogs is expected to lead to the formation of microorganisms with qualitatively novel properties. Amino-acyl tRNA synthetase is the key enzyme of amino acid recognition in the protein biosynthesis.…”

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

“…However, because of its side effects mainly on bone marrow and local phlebosclerosis, it could not make its way to the daily clinic. Over the last 15 yr, several reports singled out one alkylating peptide in the Peptichemio mixture, l ‐prolyl‐ m ‐ l ‐sarcolysyl‐ l ‐ p ‐fluoro‐phenylalanine‐ethylester (PSF), as the most cytotoxic and active in DNA cross‐linking with the most interesting results being obtained in a screen carried out in the early 1990s and revisited by the same group throughout the following years (Lewensohn et al., 1991; Hansson et al., 1991; Ehrsson et al., 1993; Larsson et al., 1998; Gullbo et al., 2003a, 2003c).…”