• DOI:10.1007/s11095-007-9249-9
• Corpus ID: 6049231

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

@article{Mittal2007ProlinePO,
  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},
  year={2007},
  volume={24},
  pages={1290-1298}
}

• S. Mittal, Xueqin Song, +1 author G. Amidon
• Published 22 March 2007
• Biology, Chemistry
• 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 cell lines using established procedures.ResultsThe bioactivation of prophalan-L in the cancer cell lines exhibited high correlation with their prolidase expression levels (r2 = 0.86). There were no significant differences in uptake of melphalan and its prodrugs. The cytotoxicity of prophalan-L (GI50) in cancer cells also showed high correlation with prolidase expression (r2 = 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 (r2 = 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.