Inhibition of poly(ADP-ribose) polymerase enhances the effect of chemotherapy in an animal model of regional therapy for the treatment of advanced extremity malignant melanoma

Hiroaki Toshimitsu, Yasunori Yoshimoto, Christina K. Augustine, James C. Padussis, Jin S. Yoo, M. Angelica Selim, Scott K. Pruitt, Henry S. Friedman, Francis Ali-Osman, Douglas Tyler

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Background: Poly(ADP-ribose) polymerase (PARP) is an important regulator of programmed cell death in response to alkylating agents such as temozolomide (TMZ). The goal of this study was to determine if a systemically administered PARP-inhibitor (INO-1001) could augment the efficacy of TMZ in a rat model of extremity malignant melanoma. Materials and Methods: PARP activity was measured in vitro across a panel of 5 human malignant melanoma-derived cell lines. To evaluate tumor response to PARP inhibition in combination with regional isolated limb infusion (ILI) therapy with TMZ, two TMZ-resistant malignant melanoma cell lines were grown as xenografts in the hind limb of rats. INO-1001 (400 mg/kg) was injected intraperitoneally 7 times every 8 hours prior to ILI. Tumor volume was measured for up to 40 days. Results: In vitro inhibition of PARP activity by INO-1001 ranged from 25.5% to 65.6%. In a mismatch repair (MMR)-deficient xenograft, treatment with INO-1001 prior to ILI significantly (P <.04) increased the efficacy of TMZ. The increase in tumor volume at day 40 following TMZ-ILI with INO-1001 was only 22.6% compared with 322.8% with TMZ-ILI alone. In a xenograft that was MMR-proficient and had high levels of O6-methylguanine-DNA methyltransferase (MGMT) activity, there was little improvement in TMZ efficacy with INO-1001 treatment. Conclusion: The PARP-inhibitor, INO-1001, can enhance the response of TMZ-resistant, MMR-deficient, malignant melanoma xenografts to intra-arterially administered TMZ in a regional treatment model of advanced extremity malignant melanoma.

Original languageEnglish (US)
Pages (from-to)2247-2254
Number of pages8
JournalAnnals of Surgical Oncology
Volume17
Issue number8
DOIs
StatePublished - Aug 2010
Externally publishedYes

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temozolomide
Poly(ADP-ribose) Polymerases
Melanoma
Extremities
Animal Models
Drug Therapy
Heterografts
DNA Mismatch Repair
Therapeutics
Tumor Burden
Cell Line
Alkylating Agents

ASJC Scopus subject areas

  • Surgery
  • Oncology
  • Medicine(all)

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Inhibition of poly(ADP-ribose) polymerase enhances the effect of chemotherapy in an animal model of regional therapy for the treatment of advanced extremity malignant melanoma. / Toshimitsu, Hiroaki; Yoshimoto, Yasunori; Augustine, Christina K.; Padussis, James C.; Yoo, Jin S.; Selim, M. Angelica; Pruitt, Scott K.; Friedman, Henry S.; Ali-Osman, Francis; Tyler, Douglas.

In: Annals of Surgical Oncology, Vol. 17, No. 8, 08.2010, p. 2247-2254.

Research output: Contribution to journalArticle

Toshimitsu, Hiroaki ; Yoshimoto, Yasunori ; Augustine, Christina K. ; Padussis, James C. ; Yoo, Jin S. ; Selim, M. Angelica ; Pruitt, Scott K. ; Friedman, Henry S. ; Ali-Osman, Francis ; Tyler, Douglas. / Inhibition of poly(ADP-ribose) polymerase enhances the effect of chemotherapy in an animal model of regional therapy for the treatment of advanced extremity malignant melanoma. In: Annals of Surgical Oncology. 2010 ; Vol. 17, No. 8. pp. 2247-2254.
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title = "Inhibition of poly(ADP-ribose) polymerase enhances the effect of chemotherapy in an animal model of regional therapy for the treatment of advanced extremity malignant melanoma",
abstract = "Background: Poly(ADP-ribose) polymerase (PARP) is an important regulator of programmed cell death in response to alkylating agents such as temozolomide (TMZ). The goal of this study was to determine if a systemically administered PARP-inhibitor (INO-1001) could augment the efficacy of TMZ in a rat model of extremity malignant melanoma. Materials and Methods: PARP activity was measured in vitro across a panel of 5 human malignant melanoma-derived cell lines. To evaluate tumor response to PARP inhibition in combination with regional isolated limb infusion (ILI) therapy with TMZ, two TMZ-resistant malignant melanoma cell lines were grown as xenografts in the hind limb of rats. INO-1001 (400 mg/kg) was injected intraperitoneally 7 times every 8 hours prior to ILI. Tumor volume was measured for up to 40 days. Results: In vitro inhibition of PARP activity by INO-1001 ranged from 25.5{\%} to 65.6{\%}. In a mismatch repair (MMR)-deficient xenograft, treatment with INO-1001 prior to ILI significantly (P <.04) increased the efficacy of TMZ. The increase in tumor volume at day 40 following TMZ-ILI with INO-1001 was only 22.6{\%} compared with 322.8{\%} with TMZ-ILI alone. In a xenograft that was MMR-proficient and had high levels of O6-methylguanine-DNA methyltransferase (MGMT) activity, there was little improvement in TMZ efficacy with INO-1001 treatment. Conclusion: The PARP-inhibitor, INO-1001, can enhance the response of TMZ-resistant, MMR-deficient, malignant melanoma xenografts to intra-arterially administered TMZ in a regional treatment model of advanced extremity malignant melanoma.",
author = "Hiroaki Toshimitsu and Yasunori Yoshimoto and Augustine, {Christina K.} and Padussis, {James C.} and Yoo, {Jin S.} and Selim, {M. Angelica} and Pruitt, {Scott K.} and Friedman, {Henry S.} and Francis Ali-Osman and Douglas Tyler",
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T1 - Inhibition of poly(ADP-ribose) polymerase enhances the effect of chemotherapy in an animal model of regional therapy for the treatment of advanced extremity malignant melanoma

AU - Toshimitsu, Hiroaki

AU - Yoshimoto, Yasunori

AU - Augustine, Christina K.

AU - Padussis, James C.

AU - Yoo, Jin S.

AU - Selim, M. Angelica

AU - Pruitt, Scott K.

AU - Friedman, Henry S.

AU - Ali-Osman, Francis

AU - Tyler, Douglas

PY - 2010/8

Y1 - 2010/8

N2 - Background: Poly(ADP-ribose) polymerase (PARP) is an important regulator of programmed cell death in response to alkylating agents such as temozolomide (TMZ). The goal of this study was to determine if a systemically administered PARP-inhibitor (INO-1001) could augment the efficacy of TMZ in a rat model of extremity malignant melanoma. Materials and Methods: PARP activity was measured in vitro across a panel of 5 human malignant melanoma-derived cell lines. To evaluate tumor response to PARP inhibition in combination with regional isolated limb infusion (ILI) therapy with TMZ, two TMZ-resistant malignant melanoma cell lines were grown as xenografts in the hind limb of rats. INO-1001 (400 mg/kg) was injected intraperitoneally 7 times every 8 hours prior to ILI. Tumor volume was measured for up to 40 days. Results: In vitro inhibition of PARP activity by INO-1001 ranged from 25.5% to 65.6%. In a mismatch repair (MMR)-deficient xenograft, treatment with INO-1001 prior to ILI significantly (P <.04) increased the efficacy of TMZ. The increase in tumor volume at day 40 following TMZ-ILI with INO-1001 was only 22.6% compared with 322.8% with TMZ-ILI alone. In a xenograft that was MMR-proficient and had high levels of O6-methylguanine-DNA methyltransferase (MGMT) activity, there was little improvement in TMZ efficacy with INO-1001 treatment. Conclusion: The PARP-inhibitor, INO-1001, can enhance the response of TMZ-resistant, MMR-deficient, malignant melanoma xenografts to intra-arterially administered TMZ in a regional treatment model of advanced extremity malignant melanoma.

AB - Background: Poly(ADP-ribose) polymerase (PARP) is an important regulator of programmed cell death in response to alkylating agents such as temozolomide (TMZ). The goal of this study was to determine if a systemically administered PARP-inhibitor (INO-1001) could augment the efficacy of TMZ in a rat model of extremity malignant melanoma. Materials and Methods: PARP activity was measured in vitro across a panel of 5 human malignant melanoma-derived cell lines. To evaluate tumor response to PARP inhibition in combination with regional isolated limb infusion (ILI) therapy with TMZ, two TMZ-resistant malignant melanoma cell lines were grown as xenografts in the hind limb of rats. INO-1001 (400 mg/kg) was injected intraperitoneally 7 times every 8 hours prior to ILI. Tumor volume was measured for up to 40 days. Results: In vitro inhibition of PARP activity by INO-1001 ranged from 25.5% to 65.6%. In a mismatch repair (MMR)-deficient xenograft, treatment with INO-1001 prior to ILI significantly (P <.04) increased the efficacy of TMZ. The increase in tumor volume at day 40 following TMZ-ILI with INO-1001 was only 22.6% compared with 322.8% with TMZ-ILI alone. In a xenograft that was MMR-proficient and had high levels of O6-methylguanine-DNA methyltransferase (MGMT) activity, there was little improvement in TMZ efficacy with INO-1001 treatment. Conclusion: The PARP-inhibitor, INO-1001, can enhance the response of TMZ-resistant, MMR-deficient, malignant melanoma xenografts to intra-arterially administered TMZ in a regional treatment model of advanced extremity malignant melanoma.

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