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.
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.


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 O(6)-methylguanine-DNA methyltransferase (MGMT) activity, there was little improvement in TMZ efficacy with INO-1001 treatment.


CONCLUSIONS
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.
Toshimitsu
Hiroaki
H
Department of Surgery, Duke University Medical Center, Durham, NC, USA.
Yoshimoto
Yasunori
Y
Augustine
Christina K
CK
Padussis
James C
JC
Yoo
Jin S
JS
Angelica Selim
M
M
Pruitt
Scott K
SK
Friedman
Henry S
HS
Ali-Osman
Francis
F
Tyler
Douglas S
DS
D000477:Alkylating Agents / Q000008:administration & dosage; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004195:Disease Models, Animal; D005121:Extremities; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000008:administration & dosage; D008545:Melanoma / Q000188:drug therapy*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051381:Rats; D011923:Rats, Nude; D012720:Severity of Illness Index; D000077204:Temozolomide; D016896:Treatment Outcome
D000477:Alkylating Agents; C491685:INO 1001; D007211:Indoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D003606:Dacarbazine; D000077204:Temozolomide