• Sachin Mittal, Xueqin Song, Balvinder S Vig, and Gordon L Amidon.
• Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA.
• Pharm. Res. 2007 Jul 1; 24 (7): 1290-8.

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 cell lines using established procedures.ResultsThe 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).ConclusionsThe 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.

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