title: Proline prodrug of melphalan, prophalan-L, demonstrates high therapeutic index in a murine melanoma model.
abstract: The therapeutic efficacy of prophalan-L, the L-proline prodrug of melphalan that demonstrated prolidase-dependent bioactivation to melphalan, was examined in vivo in a mouse melanoma model. Prophalan-L exhibited 2- to 2.5-fold higher hydrolytic and cytotoxic activity than prophalan-D, the D-analog, in B16-F10 murine melanoma cells in vitro. Prophalan-L cytotoxicity in B16-F10 cells was lower (GI50=221 microM) than that of melphalan (GI50=173 microM). The tumor growth profiles in C57BL/6J mice injected with B16-F10 cells and treated with melphalan (5.5 microg/g i.p.) and equimolar concentrations of the prodrugs demonstrated significant difference between the control (buffered saline) and melphalan or prophalan-L but no significant difference between control and prophalan-D or between melphalan and prophalan-L. Prophalan-L was significantly less toxic than melphalan, while no significant difference was observed in toxicity, measured as percent weight loss, between the prodrugs and saline control. Tumor reduction efficacy at high doses (12 microg/g i.p.) was similar for melphalan and prophalan-L; however, fatal toxicity was associated with melphalan while prophalan-L exhibited significantly lower systemic toxicity. An excellent correlation between GI50 and tumor reduction efficacy was observed for the tested drugs (r2=0.95). Prophalan-L thus demonstrates higher therapeutic index than melphalan in the murine melanoma model.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, An Arbor, MI 48109-1065, USA.
authors.forename: Sachin
authors.initials: S
authors.lastname: Mittal
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Tsume
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Landowski
authors.forename: Kyung-Dall
authors.initials: KD
authors.lastname: Lee
authors.forename: John M
authors.initials: JM
authors.lastname: Hilfinger
authors.forename: Gordon L
authors.initials: GL
authors.lastname: Amidon
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000378:metabolism / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D002151:Calorimetry; D049109:Cell Proliferation / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006868:Hydrolysis; D007202:Indicators and Reagents; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000473:pathology; D008558:Melphalan / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D011355:Prodrugs / Q000378:metabolism / Q000627:therapeutic use*; D011392:Proline / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use; D013056:Spectrophotometry, Ultraviolet; D013237:Stereoisomerism; D016019:Survival Analysis
chemical_list: D018906:Antineoplastic Agents, Alkylating; D007202:Indicators and Reagents; D011355:Prodrugs; C526265:prophalan; D011392:Proline; D008558:Melphalan