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

Sachin Mittal, Yasuhiro Tsume, Christopher P. Landowski, Kyung Dall Lee, John M. Hilfinger, Gordon L. Amidon

Research output: Contribution to journalArticleScientificpeer-review

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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 μM) than that of melphalan (GI50 = 173 μM). The tumor growth profiles in C57BL/6J mice injected with B16-F10 cells and treated with melphalan (5.5 μg/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 μg/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.

Original languageEnglish
Pages (from-to)752-758
Number of pages7
JournalEuropean Journal of Pharmaceutics and Biopharmaceutics
Volume67
Issue number3
DOIs
Publication statusPublished - 1 Nov 2007
MoE publication typeA1 Journal article-refereed

Fingerprint

Melphalan
Prodrugs
Proline
Melanoma
Therapeutics
proline dipeptidase
prophalan
Neoplasms
Poisons
Inbred C57BL Mouse
Weight Loss

Keywords

  • Melphalan
  • Mouse melanoma model
  • Prodrug
  • Prolidase
  • Therapeutic efficacy

Cite this

Mittal, Sachin ; Tsume, Yasuhiro ; Landowski, Christopher P. ; Lee, Kyung Dall ; Hilfinger, John M. ; Amidon, Gordon L. / Proline prodrug of melphalan, prophalan-l, demonstrates high therapeutic index in a murine melanoma model. In: European Journal of Pharmaceutics and Biopharmaceutics. 2007 ; Vol. 67, No. 3. pp. 752-758.
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Proline prodrug of melphalan, prophalan-l, demonstrates high therapeutic index in a murine melanoma model. / Mittal, Sachin; Tsume, Yasuhiro; Landowski, Christopher P.; Lee, Kyung Dall; Hilfinger, John M.; Amidon, Gordon L.

In: European Journal of Pharmaceutics and Biopharmaceutics, Vol. 67, No. 3, 01.11.2007, p. 752-758.

Research output: Contribution to journalArticleScientificpeer-review

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AU - Mittal, Sachin

AU - Tsume, Yasuhiro

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AU - Hilfinger, John M.

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