Proline prodrug of melphalan targeted to prolidase, a prodrug activating enzyme overexpressed in melanoma.

Abstract

PURPOSE:

To 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 METHODS:

Hydrolysis, 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 cell lines using established procedures.

RESULTS:

The bioactivation of prophalan-L: in the cancer cell lines exhibited high correlation with their prolidase expression levels (r (2) = 0.86). There were no significant differences in uptake of melphalan and its prodrugs. The cytotoxicity of prophalan-L: (GI(50)) in cancer cells also showed high correlation with prolidase expression (r (2) = 0.88), while prophalan-D: was ineffective at comparable concentrations. A prolidase targeting index (ratio of melphalan to prophalan-L: cytotoxicity normalized to their uptake) was computed and showed high correlation with prolidase expression (r (2) = 0.82).

CONCLUSIONS:

The data corroborates the specificity of prophalan-L: activation by prolidase as well as prolidase-targeted cytotoxicity of prophalan-L: in cancer cell lines. Hence, prophalan-L: , a stable prodrug of melphalan, exhibits potential for efficiently targeting melanoma with reduced systemic toxicity.

• Authors: Sachin Mittal, Xueqin Song, Balvinder S Vig, Gordon L Amidon
• Journal: Pharmaceutical research (Pharm Res) Vol. 24 Issue 7 Pg. 1290-8 (Jul 2007) ISSN: 0724-8741 [Print] United States
• PMID: 17377743 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Alkylating
• Prodrugs
• Protease Inhibitors
• RNA, Messenger
• carbobenzoxyproline
• Chlorambucil
• Proline
• Dipeptidases
• proline dipeptidase
• Melphalan

Topics

• Antineoplastic Agents, Alkylating (chemistry, metabolism, pharmacology)
• Biological Transport
• Biotransformation
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Chlorambucil (metabolism)
• Dipeptidases (antagonists & inhibitors, genetics, metabolism)
• Dose-Response Relationship, Drug
• Gene Expression Regulation, Enzymologic (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Hydrolysis
• Inhibitory Concentration 50
• Melanoma (enzymology, genetics, metabolism, pathology)
• Melphalan (analogs & derivatives, chemistry, metabolism, pharmacology)
• Prodrugs (chemistry, metabolism, pharmacology)
• Proline (analogs & derivatives, chemistry, metabolism, pharmacology)
• Protease Inhibitors (pharmacology)
• RNA, Messenger (metabolism)
• Stereoisomerism