Genz-644282 

Twenty-nine established human tumor cell lines are exposed to a concentration range of Genz-644282 in two-four independent experiments. Human tumor cell lines representing a range of histology and potential resistance mechanisms includ MIA PaCa-2, AsPC-1, BxPC-3, CFPAC-1, Hs766T and Capan-1 pancreatic cancers, MEL624, C32, Hs695T and SK-MEL-3 melanomas, NCI-H1299, NCI-H292, NCI-H1915 and SW900 non-small cell lung cancers, HCC1395, HCC1937, HCC202, Hs578T, T-47D and ZR-75-1 breast cancer, ACHN, 769-P, A-498, A-704, SW156, Caki-2 and TK-10 renal cancers and OVCAR-4 and OVCAR-5 ovarian cancers. Cells are plated at 4 × 10³/well in 96-well tissue culture plates in 100 µL RPMI medium supplemented with 5% FBS and 12 concentrations of Genz-644282 from 0.1 nM to 10 µM, with each concentration tested in triplicate. Plates are incubated overnight at 37ºC in humidified air with 5% CO₂. Plates are incubated with Genz-644282 at 37ºC with humidified air/5% CO₂ for 72 hrs. After the incubation period, the test plates are read utilizing Cell Titer-Glo Luminescent Cell Viability Assay. Luminescence is measured with a Synergy HT plate reader utilizing the associated ineticalc software, Version #3.4. Luminescence data are converted to growth fraction by comparison to the luminescence for the untreated control for each cell line and IC₅₀ and IC₉₀ values determined from the graphical data. Each cell line is tested in t least two independent experiments^[1].

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Nu/nu mice are implanted subcutaneously with a 4 mm³ tumor fragment, and treatments are initiated when tumors reach 200 mm³. Compounds are prepared freshly prior to injection, with Genz-644282 is formulated in M/6 lactate, irinotecan in D5W (5% Dextrose, aqueous), gemcitabine in saline, and docetaxel in ethanol, Cremophor EL and saline. Genz-644282 is compared with irinotecan in experiments with the human HCT-116, HT-29, HCT-15 and DLD-1 colon carcinoma and 786-O renal cell carcinoma xenografts. Irinotecan is administered at 60 mg/kg/day by IV injection every fourth day for three injections. Genz-644282 is compared with docetaxel in the human CIH460 non-small cell lung carcinoma xenograft. Docetaxel is administered at 12, 16 or 20 mg/kg/day by IV injection on alternate days for three injections. Genz-644282 is compared with dacarbazine in the human LOX-IMVI melanoma xenograft. Dacarbazine is administered at 90 mg/kg/day by IP injection once daily for 5 days. Genz-644282 is administered at 1, 1.36, 1.7, 2.7 or 4.1 mg/kg/day by IV on alternate days 3-times per week for 2 weeks in all in vivo experiments^[1].

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

• [1]. Kurtzberg LS, et al. Genz-644282, a novel non-camptothecin topoisomerase I inhibitor for cancer treatment. Clin Cancer Res. 2011 May 1;17(9):2777-87.  [Content Brief]

  [2]. Houghton PJ, et al. Testing of the topoisomerase 1 inhibitor Genz-644282 by the pediatric preclinical testing program. Pediatr Blood Cancer. 2012 Feb;58(2):200-9.  [Content Brief]

  [3]. Sooryakumar D, et al. Molecular and cellular pharmacology of the novel noncamptothecin topoisomerase I inhibitor Genz-644282. Mol Cancer Ther. 2011 Aug;10(8):1490-9.  [Content Brief]