Genz-644282 is a non-camptothecin topoisomerase I inhibitor, used for cancer research.

Genz-644282 is a topoisomerase I inhibitor. Genz-644282 shows potent activities against 29 human tumor cell lines with IC₅₀s ranging from 1.8 nM to 1.8 μM^[1]. Genz-644282 suppresses the PPTP cell lines, with IC₅₀s of 0.2-21.9 nM, and the mean IC₅₀ value is 1.2 nM^[2]. Genz-644282 is potent at trapping Top1-DNA covalent cleavage complexes. Genz-644282 (0.1 μM) induces γH2AX foci in human colon cancer HCT116 cells and breast cancer MCF7 cells. Genz-644282 is cytotoxic on the CPT-resistant human cancer cell lines^[3].

上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.

Genz-644282 (1-4 mg/kg) is active when administered intravenously to the mice. Genz-644282 (2.7 mg/kg, i.v.) causes tumor growth delay (TGD) of 34 days in the human HCT-116 colon cancer xenograft, 27 days in the human HT-29 colon carcinoma xenograft and mice bearing the NCI-H460 human non-small cell lung carcinoma. Genz-644282 (2 mg/kg, i.v.) results in a TGD of 33 days in the human HCT-15 colon carcinoma xenograft, and 28 days in mice bearing LOX-IMVI melanoma. Moreover, Genz-644282 (1 mg/kg, i.v.) leads to 14 days of TGD in mice bearing the DLD-1 human colon carcinoma xenograft. Genz-644282 (1.7 mg/kg, i.v.) also produces a TGD of 23 days in mice bearing 786-O tumors and 33 days in NCI-H1299 human non-small cell lung carcinoma xenograft^[1]. Genz644282 at maximum tolerated dose (MTD, 4 mg/kg) results in maintained complete responses (MCR) in 6/6 evaluable solid tumor models. Genz644282 (2 mg/kg) induces CR or MCR in 3/3 tumor models and causes objective regressions in 7 of 17 (41%) models, but there are no objective responses at 1 mg/kg^[2].

上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.

407.42

C₂₂H₂₁N₃O₅

529488-28-6

Room temperature in continental US; may vary elsewhere.

4°C, protect from light

*In solvent : -80°C, 6 months; -20°C, 1 month (protect from light)

DMSO : 3.64 mg/mL (8.93 mM; ultrasonic and warming and heat to 75°C)

请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。
储备液的保存方式和期限：-80°C, 6 months; -20°C, 1 month (protect from light)。-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。

请根据您的实验动物和给药方式选择适当的溶解方案。以下溶解方案都请先按照 In Vitro 方式配制澄清的储备液，再依次添加助溶剂：

——为保证实验结果的可靠性，澄清的储备液可以根据储存条件，适当保存；体内实验的工作液，建议您现用现配，当天使用； 以下溶剂前显示的百
分比是指该溶剂在您配制终溶液中的体积占比；如在配制过程中出现沉淀、析出现象，可以通过加热和/或超声的方式助溶

• 1.

  请依序添加每种溶剂： 10% DMSO    90% (20% SBE-β-CD in saline)

  Solubility: ≥ 2.5 mg/mL (6.14 mM); Clear solution

  此方案可获得 ≥ 2.5 mg/mL (6.14 mM，饱和度未知) 的澄清溶液。

  以 1 mL 工作液为例，取 100 μL 25.0 mg/mL 的澄清 DMSO 储备液加到 900 μL 20% 的 SBE-β-CD 生理盐水水溶液中，混合均匀。

  将 2 g 磺丁基醚 β-环糊精加入 5 mL 生理盐水中，再用生理盐水定容至 10 mL，完全溶解，澄清透明
• 2.

  请依序添加每种溶剂： 10% DMSO    90% corn oil

  Solubility: ≥ 2.5 mg/mL (6.14 mM); Clear solution

  此方案可获得 ≥ 2.5 mg/mL (6.14 mM，饱和度未知) 的澄清溶液，此方案不适用于实验周期在半个月以上的实验。

  以 1 mL 工作液为例，取 100 μL 25.0 mg/mL 的澄清 DMSO 储备液加到 900 μL玉米油中，混合均匀。

• [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.

  [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.

  [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.

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].

上海金畔生物科技有限公司 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].

上海金畔生物科技有限公司 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.

  [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.

  [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.