Rubitecan
(Synonyms: 鲁比特康,RFS 2000; 9-Nitrocamptothecin) 目录号 : GC37571
A DNA topoisomerase I inhibitor
Cas No.:91421-42-0
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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Rubitecan is a DNA topoisomerase I inhibitor.1,2 It inhibits DNA topoisomerase I and increases the fraction of supercoiled DNA in a cell-free assay in a concentration-dependent manner.1 Rubitecan inhibits the growth of A121 ovarian and H460 lung cancer cells (IC50s = 4 and 2 nM, respectively).3 It also inhibits the growth of doxorubicin-susceptible and -resistant MCF-7 breast cancer cells (IC50s = 2 and 3 nM, respectively). Rubitecan (4 mg/kg twice per week) reduces tumor growth in a U937 leukemia mouse xenograft model.4
1.Rubin, E., Pantazis, P., Bharti, A., et al.Identification of a mutant human topoisomerase I with intact catalytic activity and resistance to 9-nitro-camptothecinJ. Biol. Chem.269(4)2433-2439(1994) 2.Hinz, H.R., Harris, N.J., Natelson, E.A., et al.Pharmacokinetics of the in vivo and in vitro conversion of 9-nitro-20(S)-camptothecin to 9-amino-20(S)-camptothecin in humans, dogs, and miceCancer Res.54(12)3096-3100(1994) 3.Bernacki, R.J., Pera, P., Gambacorta, P., et al.In vitro antitumor activity of 9-nitro-camptothecin as a single agent and in combination with other antitumor drugsAnn. N. Y. Acad. Sci.922293-297(2000) 4.Pantazis, P., Mendoza, J.T., Early, J.A., et al.9-Nitro-camptothecin delays growth of U-937 leukemia tumors in nude mice and is cytotoxic or cytostatic for human myelomonocytic leukemia lines in vitroEur. J. Haematol.50(2)81-89(1993)
| Cas No. | 91421-42-0 | SDF | |
| 别名 | 鲁比特康,RFS 2000; 9-Nitrocamptothecin | ||
| Canonical SMILES | O=C1[C@](O)(CC)C2=C(CO1)C(N3CC4=CC5=C([N+]([O-])=O)C=CC=C5N=C4C3=C2)=O | ||
| 分子式 | C20H15N3O6 | 分子量 | 393.35 |
| 溶解度 | DMSO: 125 mg/mL (317.78 mM) | 储存条件 | Store at -20°C |
| General tips | 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 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.5423 mL | 12.7113 mL | 25.4227 mL |
| 5 mM | 0.5085 mL | 2.5423 mL | 5.0845 mL |
| 10 mM | 0.2542 mL | 1.2711 mL | 2.5423 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Rubitecan
Expert Opin Investig Drugs 2006 Jan;15(1):71-9.PMID:16370935DOI:10.1517/13543784.15.1.71.
The only approved camptothecins for use in patients to date (topotecan and irinotecan) are delivered intravenously. Thus, an oral camptothecin analogue that would provide the convenience of oral delivery with the flexibility for a variety of prolonged treatment schedules would be advantageous. Rubitecan is an orally available camptothecin analogue that also has potential for delivery transdermally or by inhalation. Like all of the camptothecins, its antitumour activity is mediated through the inhibition of DNA topoisomerase I, which is involved in relaxing supercoiled DNA, which is important for the process of DNA replication and RNA transcription. Rubitecan exists in equilibrium as 9-nitro-camptothecin (9-NC) and 9-amino-camptothecin (9-AC), a metabolite that is thought to be active although it failed in clinical trials. Both 9-NC and 9-AC contain a lactone ring that is required for optimal activity with the carboxylic acid (open ring) forms being significantly less active or inactive. A more acidic environment favours the lactone ring structure, whereas neutral or basic conditions favour the conversion to the carboxylic acid form. In addition to issues of lactone ring stability at physiological pH (true for all of the camptothecin analogues), there is pharmacokinetic variability that has had to be dealt with during the development of Rubitecan. Preclinically, Rubitecan has shown activity against a broad spectrum of tumour types in in vitro and in vivo human tumour xenograft models. Frustratingly, the level of activity of an agent in preclinical models has not always translated into similar activity against human tumours in clinical trials. To date, with the exception of pancreatic and possibly ovarian cancer, Rubitecan has had disappointing activity against a number of other solid tumours in relatively small Phase I/II trials; however, it has shown sufficient activity against pancreatic cancer, a malignancy that remains difficult to treat, to continue to be evaluated in clinical trials for this indication. Results of clinical trials in the next few years should determine whether Rubitecan can find a role in cancer therapy.
Rubitecan: 9-NC, 9-Nitro-20(S)-camptothecin, 9-nitro-camptothecin, 9-nitrocamptothecin, RFS 2000, RFS2000
Drugs R D 2004;5(5):305-11.PMID:15357630DOI:10.2165/00126839-200405050-00007.
Rubitecan [Orathecin, 9-nitrocamptothecin, 9NC, RFS 2000] is a topoisomerase I inhibitor extracted from the bark and leaves of the Camptotheca acuminata tree, which is native to China. Rubitecan is an oral compound being developed for the treatment of pancreatic cancer and other solid tumours by SuperGen. One of the major benefits of Rubitecan is that it can be administered in an outpatient setting, so patients can be treated in their homes. Rubitecan was isolated by the Stehlin Foundation in the US. SuperGen is currently awaiting regulatory approval in the US and the EU for Rubitecan in the treatment of pancreatic cancer. At the BIO-2004 conference, SuperGen announced it is seeking a partner for Rubitecan for territories outside the US. SuperGen acquired exclusive worldwide rights to Rubitecan from the Stehlin Foundation in 1997 except in Mexico, Canada, Spain, Japan, the UK, France, Italy and Germany. SuperGen has also received approval from the US FDA to use its own manufactured Rubitecan in clinical trials. SuperGen and the Stehlin Foundation have an 8-year research agreement that secures global rights to other camptothecins and additional anticancer compounds for the former. In December 1999, SuperGen and Abbott signed a worldwide sales and marketing agreement for Rubitecan. Under the terms of the agreement, Abbott had exclusive distribution and promotion rights for Rubitecan outside the US, and co-promotion rights with SuperGen within the US. In return, Abbott made an initial equity investment in SuperGen. SuperGen and Abbott Laboratories ended their collaboration agreement in February 2002 by mutual consent with SuperGen stating that the dissolution of the agreement was based on commercial motivation rather than anything to do with Rubitecan's safety or efficacy. Abbott no longer has rights or obligations to purchase shares of SuperGen stock or an option to purchase up to 49% of the company. For its part, SuperGen will no longer receive milestone payments worth up to $US57 million. SuperGen has formed a clinical and business alliance with US Oncology (created by the merger between American Oncology Resources and Physician Reliance Network in the US), and will collaborate on clinical trials of Rubitecan. SuperGen believes that this relationship will increase the patient population available for trials and enable it to market the drug directly to Oncologists. SuperGen and Capital Research and Management Company have completed a $US16.6 million private placement transaction that will enable future funding for the Rubitecan programme as well as other oncology programmes. In July 2004, SuperGen's European subsidiary, EuroGen Pharmaceuticals, submitted a Marketing Authorisation Application for Rubitecan in the treatment of pancreatic cancer. The application will be reviewed under the EMEA Centralised Procedure. In June 2003, the EMEA granted SuperGen orphan drug status for Rubitecan for the treatment of pancreatic cancer. The US FDA has also granted orphan drug status for Rubitecan in the treatment of pancreatic cancer and fast-track status for Rubitecan for the treatment of locally advanced or metastatic pancreatic cancer that is resistant or refractory to chemotherapy. SuperGen has conducted three phase III pivotal trials in patients with pancreatic cancer. A phase III randomised trial in chemotherapy-naive patients was conducted at 132 centres throughout the US. The trial enrolled approximately 994 patients who were randomised to receive Rubitecan or gemcitabine. Enrollment was completed in October 2001. Another phase III trial has compared Rubitecan with the most appropriate chemotherapy in chemotherapy-resistant patients. Enrollment of over 400 patients at 200 medical centres across the US was completed in June 2001. Results from the trial were presented at the 39th Annual Meeting of the American Society of Clinical Oncology (ASCO-2003) [Chicago, US; 31 May - 3 June 2003], after they had been compiled, analysed and submitted to the FDA. The results of the study showed that Rubitecan could not help all chemotherapy-resistant patients, but could increase survival in those that do respond. The other phase III pivotal trial was conducted in patients with pancreatic cancer who had failed treatment with gemcitabine. This trial completed enrollment in October 2001, and had enrolled approximately 448 patients. SuperGen is conducting phase II trials of Rubitecan in patients with solid tumours in the UK, Italy, France, Germany, the Netherlands and Denmark. Each trial will enroll 100-150 patients with various tumour types, including colorectal, lung, breast, gastric, prostate, cervical and head and neck cancers. Phase I/II trials are underway to investigate Rubitecan as a radiosensitiser in patients with lung cancer, and phase II trials in patients with breast cancer are also being conducted. A phase II study in ovarian cancer patients is also being conducted. Results from an ongoing phase II study in cancer patients have shown that Rubitecan was effective against chordomas, a rare type of bone cancer. Phase II studies are also underway in haematological malignancies including myelodysplastic syndrome (preleukaemia) and chronic myelomonocytic leukaemia. In February 2000, SuperGen announced that its IND submission for Rubitecan had been approved by the Therapeutics Products Programme of Canada. The company stated that it intended to begin clinical trials in Canada in the near future. In February 2004, SuperGen announced an offering of shares of its common stock to finance the commercialisation of Rubitecan capsules. In July 2003, SuperGen was granted a US patent covering combination therapies with chemotherapeutic anthracycline agents and structural modifications that may one day lead to next-generation Rubitecan compounds. In December 2002, SuperGen was granted US patent No. 6,482,830, covering its polymorphic formulations of Rubitecan. The patent also covers a class of polymorphs that are similar to the one at the centre of Rubitecan. In addition, SuperGen was also issued US patent No. 6,485,514 in December 2002, covering the local delivery of Rubitecan via stents and/or catheters to sites of proliferating cells. Stent- or catheter-delivered Rubitecan may be beneficial in certain types of cardiac procedures, such as ablation or angioplasty, as well as for direct injection into a certain number of solid tumours. SuperGen is also developing an inhaled, liposomal formulation of Rubitecan. It acquired the worldwide rights to this formulation from the Clayton Foundation in December 1999. Inhaled Rubitecan is in clinical trials in the US for the treatment of lung cancer and pulmonary metastatic cancer.
Phase II study of Rubitecan, an oral camptothecin in patients with advanced colorectal cancer who have failed previous 5-fluorouracil based chemotherapy
Invest New Drugs 2006 Jul;24(4):359-63.PMID:16525767DOI:10.1007/s10637-006-6451-2.
Background: Rubitecan (RFS-2000, 9NC, Orathecin) is an orally bioavailable camptothecin analogue, with evidence of preclinical activity in colon cancer cell lines. We evaluated oral Rubitecan (5 days on, 2 days rest per week) on a continuous schedule, in patients with advanced colorectal cancer (CRC), who progressed after 5-fluorouracil based chemotherapy. Patients and results: Fourteen eligible patients were treated with Rubitecan at 1.5 mg/m2/day on a 5 day/week continuous schedule. Therapy was well tolerated with most adverse events in the mild to moderate category. Grade 3/4 toxicity consisting of anemia, diarrhea and elevated bilirubin was seen in 4 patients. No responses were seen in 13 evaluable patients. Overall median survival (95% confidence interval) was 10.1 (range 3.1-12.6) months, and median time to progression was 2.1 months. Conclusions: Administration of Rubitecan was well tolerated, but this schedule does not appear to have clinical activity in patients with advanced previously treated CRC.
Phase II trial of oral Rubitecan in previously treated pancreatic cancer patients
Oncologist 2005 Mar;10(3):183-90.PMID:15793221DOI:10.1634/theoncologist.10-3-183.
Background: Additional systemic treatments for locally advanced or metastatic pancreatic cancer are needed, as current treatment options produce only modest survival benefits. Rubitecan (Orathecin; Supergen Inc., Dublin, CA, http://www.supergen.com) is an orally active camptothecin derivative with demonstrated responses in patients with pancreatic cancer in early clinical trials. This phase II, open-label trial was developed to assess the safety and efficacy of Rubitecan in patients with locally advanced or metastatic pancreatic cancer refractory to conventional chemotherapy. Methods: Fifty-eight patients with failed or relapsed advanced pancreatic cancer after receiving at least one prior chemotherapy regimen were enrolled to receive eight consecutive weeks of treatment with Rubitecan at a dose of 1.5 mg/m2 orally on five consecutive days per week, followed by 2 days off therapy, repeatedly. The primary end point was response rate. Time to progression, overall survival, changes in CA19-9 levels, and the composite measure of clinical benefit response were evaluated as secondary end points. Results: Among 43 patients with measurable disease, 7% (3/43) achieved partial responses and 16% (7/43) had disease stabilization for an overall response and disease stabilization rate of 23%. All responses were confirmed by independent radiology review. Median survival was longer in responding patients than in the overall study cohort (10 months versus 3 months). Gastrointestinal and hematologic toxicities were the most commonly reported adverse events. Conclusion: Oral Rubitecan produced responses and was well tolerated by heavily pretreated patients with refractory pancreatic cancer. The overall risk-benefit profile of oral Rubitecan appears promising, supporting further evaluation in phase III trials in patients with refractory and chemotherapy-naive pancreatic cancer.
Phase I study of Rubitecan and gemcitabine in patients with advanced malignancies
Ann Oncol 2002 Nov;13(11):1819-25.PMID:12419757DOI:10.1093/annonc/mdf342.
Background: Rubitecan (9-nitrocamptothecin, 9-NC, Orathecin) and gemcitabine have single-agent activity in pancreatic and ovarian carcinoma. We conducted a phase I trial to evaluate the maximum tolerated dose (MTD) and toxicities of this combination in advanced malignancies. Patients and methods: Twenty-one patients with refractory or recurrent malignancies were enrolled in this dose escalation trial. Dose escalation proceeded from a starting level of Rubitecan at 0.75 mg/m(2)/day administered orally on days 1-5 and 8-12 in combination with gemcitabine 1000 mg/m(2) administered intravenously on days 1 and 8 of a 21-day cycle. Results: The MTD was defined as Rubitecan 1 mg/m(2) administered orally days 1-5 and 8-12, and gemcitabine 1000 mg/m(2) administered intravenously over 30 min days 1 and 8, given every 21 days. Dose-limiting toxicity was myelosuppression including neutropenia and thrombocytopenia. Other side effects included diarrhea, nausea, vomiting and fatigue. Five patients with stable disease were observed among 18 evaluable patients. Conclusions: The recommended phase II dose is Rubitecan 1 mg/m(2) given orally on days 1-5 and 8-12 in combination with gemcitabine 1000 mg/m(2) as a 30-min intravenous infusion on days 1 and 8 of a 21-day cycle.