Proline Prodrug of Melphalan Targeted to Prolidase, a Prodrug Activating Enzyme Overexpressed in Melanoma

  title={Proline Prodrug of Melphalan Targeted to Prolidase, a Prodrug Activating Enzyme Overexpressed in Melanoma},
  author={Sachin Mittal and Xueqin Song and Balvinder S. Vig and Gordon L Amidon},
  journal={Pharmaceutical Research},
PurposeTo determine the bioactivation and uptake of prolidase-targeted proline prodrugs of melphalan in six cancer cell lines with variable prolidase expression and to evaluate prolidase-dependence of prodrug cytotoxicity in the cell lines compared to that of the parent drug, melphalan.Materials and MethodsHydrolysis, cell uptake, and cell proliferation studies of melphalan and the L- and D-proline prodrugs of melphalan, prophalan-L and prophalan-D, respectively, were conducted in the cancer… 

Proline prodrug of melphalan, prophalan-L, demonstrates high therapeutic index in a murine melanoma model.

Liposomal Formulation of a Melphalan Lipophilic Prodrug: Studies of Acute Toxicity, Tolerability, and Antitumor Efficacy.

Lower toxicity of the liposomal formulation of MlphDG promises improved quality of life for cancer patients in need of treatment with melphalan and list of indications formelphalan therapy could be extended.

Melphalan: Recent insights on synthetic, analytical and medicinal aspects.

Targeting the delivery of glycan-based paclitaxel prodrugs to cancer cells via glucose transporters.

These glycan-based prodrugs may be good drug candidates for cancer therapy, and the glycan conjugation approach is an alternative method to enhance the targeted delivery of other drugs to cancer cells that overexpress GLUTs.

Amino acids as promoieties in prodrug design and development.

Current Understanding of the Emerging Role of Prolidase in Cellular Metabolism

An in-depth understanding of prolidase as a dipeptidase and protein regulating the function of key biomolecules in cellular metabolism is provided.

Design and evaluation of cyclodextrin-based delivery systems to incorporate poorly soluble curcumin analogs for the treatment of melanoma.

  • D. MichelJ. Chitanda I. Badea
  • Biology, Chemistry
    European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V
  • 2012

Prolidase function in proline metabolism and its medical and biotechnological applications

The many in vivo functions of procaryotic and eucaryotic prolidases, as well as the most recent advances in therapeutic and biotechnological application of prolidase are discussed.



Proline analogue of melphalan as a prolidase-convertible pro-drug in breast cancer MCF-7 cells.

It has been found that Mel-pro is more effectively transported into the MCF-7 cells, evokes higher cytotoxicity, lower antimitotic activity and collagen-inhibiting activity, compared to Mel, suggesting that targeting of prolidase as a pro-drug-converting enzyme may serve as a potential strategy in pharmacotherapy of breast cancer.

Prolidase, a potential enzyme target for melanoma: design of proline-containing dipeptide-like prodrugs.

Melphalan prodrugs such as prophalan-l that are cleavable by Prolidase offer the potential for enhanced selectivity by facilitating cytotoxic activity only in cells overexpressing prolidase.

Prolidase as a prodrug converting enzyme I. Synthesis of proline analogue of chlorambucil and its susceptibility to the action of prolidase.

Although insolubility of the proline analogue of chlorambucil in aqueous solutions limit its potential therapeutic value, the presented data suggest that prolidase may have a broader substrate specificity and suggest that targeting of prolid enzyme as a prodrug-converting enzyme may serve as a novel strategy in therapy of various diseases.

Utilization of peptide carrier system to improve intestinal absorption: targeting prolidase as a prodrug-converting enzyme.

Results demonstrate that prolidase may serve as a prodrug-converting enzyme for the dipeptide-type prodrugs, utilizing the peptide carrier for transport of pro drugs into the mucosal cells and prolid enzyme, a cytosolic enzyme, to release the drug.

Inhibition and active-site modelling of prolidase.

Analysis of inhibitor action and consideration of X-ray crystallographic data of relevant Mn2+ complexes allowed the active-site model of prolidase to be further refined; a new model is presented in which the substrate acts as a bidentate ligand towards theactive-site manganous ion.

Characterization of CPT-11 hydrolysis by human liver carboxylesterase isoforms hCE-1 and hCE-2.

Data indicate that hCE-2 is a high-affinity, high-velocity enzyme with respect to CPT-11, and likely plays a substantial role in C PT-11 activation in human liver at relevant pharmacological concentrations.

Cellular mechanisms of multidrug resistance of tumor cells.

Cellular drug resistance is mediated by different mechanisms operating at different steps of the cytotoxic action of the drug from a decrease of drug accumulation in the cell to the abrogation of apoptosis induced by the chemical substance.

Proline-dependent structural and biological properties of peptides and proteins.

  • A. YaronF. Naider
  • Biology, Chemistry
    Critical reviews in biochemistry and molecular biology
  • 1993
A critical analysis of peptidases involved in the cleavage of proline-containing peptide bonds reveals that they may function as key pacemakers in the control of the activity of many peptide hormones and that they are involved in a variety of immunological processes, including T-cell-mediated immune response.