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A PRECLINICAL Evaluation Of ZIO-201 (ISOPHOSPHORAMIDE Mustard (IPM)-lysine) In Sarcoma.

A PRECLINICAL Evaluation Of ZIO-201 (ISOPHOSPHORAMIDE Mustard (IPM)-lysine) In Sarcoma. E.Anders Kolb, Pooja Gidwani, Robert Peter Gale, Richard Gorlick. Isophosphoramide Mustard-lysine (Zio-201). IPM: active moiety of ifosfamide. Alkylator: crosslinks DNA via G:C base pairs irreversibly.

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A PRECLINICAL Evaluation Of ZIO-201 (ISOPHOSPHORAMIDE Mustard (IPM)-lysine) In Sarcoma.

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  1. A PRECLINICAL Evaluation Of ZIO-201 (ISOPHOSPHORAMIDE Mustard (IPM)-lysine) In Sarcoma. E.Anders Kolb, Pooja Gidwani, Robert Peter Gale, Richard Gorlick

  2. Isophosphoramide Mustard-lysine (Zio-201) • IPM: active moiety of ifosfamide. • Alkylator: crosslinks DNA via G:C base pairs irreversibly. • Activity: variety of cancers. • Unstable for clinical administration. • Lysine: provides stability.

  3. Metabolism of Oxazaphosphorines

  4. Ifosfamide Versus Zio-201 IFOS Acrolein “bladder toxicity” Chloroacetaldehyde “fuzzy brain” X X Zio-201 Courtesy of Ziopharm

  5. Advantages of Zio-201 • Effective • No toxic metabolites (acrolein, CAA) • Bypassing resistance mechanisms (ALDH over-expression)

  6. Objectives • To test the activity of Zio-201 in a broad variety of sarcomas in-vitro. • To test the activity of Zio-201 in sarcoma tumor xenografts including cyclophosphamide resistant tumors.

  7. Zio-201 has Broad Activity in Sarcoma Lines In Vitro a. Rhabdomyosarcoma b. Ewing’s Sarcoma d. Synovial Sarcoma c. Osteosarcoma

  8. In Vitro, in most lines evaluated, the IC50 of daily x1 and daily x3 dosing are comparable OS229-Osteosarcoma RH30-Rhabdomyosarcoma

  9. In Vitro, in most lines evaluated, the IC50 of daily x1 and daily x3 dosing are comparable

  10. In the OS31 osteosarcoma tumor line, Zio-201 at the MTD for each dose schedule results in significant tumor growth delay p=0.09

  11. Cyclophosphamide resistance in Osteosarcoma Lines OS31 OS33 Houghton PJ, Morton CL, Tucker C, Payne D, Favours E, Gorlick R, Kolb EA, Zhang W, Lock R, Carol H, Tajbakhsh M, Reynolds CP, Maris JM, Courtright J, Keir ST, Friedman HS, Stopford C, Zeidner J, Wu1 J, Liu T, Billups CA, Khan J, Ansher S, Zhang J, Smith MA. The Pediatric Preclinical Testing Program: Description of Models and Early Testing Results. Pediatric Blood and Cancer (in press)

  12. OS160 OS33 OS17 OS2 OS29 OS31 OS9 OS1 ALD3A1 Aldehyde dehydrogenase 3A1 is differentially expressed in cyclophosphamide-resistant lines compared to sensitive lines Affy U133a Micorarray data courtesy of Peter Houghton, PI, Pediatric Preclinical Testing Program, St. Judes Children’s Research Hospital

  13. 0 1 2 3 4 5 6 Zio-201 is active in the cyclophosphamide-resistant, ALD3A1-overexpressing OS31 line

  14. Summary • Zio-201 has broad activity in sarcomas in-vitro. • In many cell lines, IC50 for daily x1 and daily x3 dosing are comparable. • Significant responses are noted in OS 31 osteosarcoma tumor line in-vivo at both daily x1 and daily x3 dosing.

  15. Summary • ALD3A1 is overexpressed in cyclophosphamide resistant tumors (OS31, OS2) suggesting this as a potential mechanism of resistance. • IPM-lysine is active in cyclophosphamide resistant OS31 line.

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