AG14361 is a novel poly (ADP-ribose) polymerase-1 inhibitor with a GI50 of 10.9 µM. AG14361 enhances temozolomide activity in all MMR-proficient cells (1.5–3.3-fold) but is more effective in MMR-deficient cells (3.7–5.2-fold potentiation), overcoming temozolomide resistance. AG14361 significantly potentiated camptothecin-mediated cytotoxicity in all cells, except the base excision repair–deficient EM9 cells. In the breast cancer cell lines, AG14361 had no effect on IR-induced degradation of IkappaBalpha or nuclear translocation of p50 or p65. However, AG14361 inhibited IR-induced NF-kappaB-dependent transcription of a luciferase reporter gene.
|Cell lines||LoVo, A549, and SW620 cells|
|Preparation method||Cell growth inhibition was estimated in exponentially growing LoVo, A549, and SW620 cells in 96-well plates. Cells were exposed to temozolomide (0–1000 μM, see Fig. 4, A) or topotecan (0–30 nM, see Fig. 4, B) in the presence or absence of 0.4 μM AG14361. Cells were also exposed to AG14361 (0–20 μM, see Fig. 4, C) alone or in the presence of 400 μM temozolomide. After 5 days of culture, these cells were fixed with 10% trichloroacetic acid and stained with sulforhodamine B (28). The concentration of temozolomide, topotecan, and AG14361 alone or in combination that inhibited growth by 50% (GI50) was calculated from computer-generated curves.|
|Incubation time||5 days|
|Animal models||CD-1 nude mice bearing palpable, subcutaneous SW620 or LoVo xenografts|
|Dosages||5 or 15 mg/kg daily for 5 days|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO ≥20 mg/mL|
Inhibition of poly(ADP-ribose) polymerase (PARP) and ataxia telangiectasia mutated (ATM) on the chemosensitivity of mantle cell lymphoma to agents that induce DNA strand breaks.
Golla et al. Hematol Oncol. 2011 Dec 14. PMID: 22170260.
Exploiting the Achilles heel of cancer: the therapeutic potential of poly(ADP-ribose) polymerase inhibitors in BRCA2-defective cancer.
Kyle et al. Br J Radiol. 2008 Oct;81 Spec No 1:S6-11. PMID: 18820000.
Preclinical selection of a novel poly(ADP-ribose) polymerase inhibitor for clinical trial.
Thomas et al. Mol Cancer Ther. 2007 Mar;6(3):945-56. PMID: 17363489.
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