Pyrazoloacridine
(Synonyms: NSC366140无结构图,NSC 366140; PD 115934) 目录号 : GC61224
Pyrazoloacridine(NSC366140)具有抗癌活性，抑制拓扑异构酶1和2的活性(topoisomerases1and2)。Pyrazoloacridine(NSC366140)对K562髓系白血病细胞中的IC50值为1.25μM(24h)。
Cas No.:99009-20-8
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Pyrazoloacridine (NSC 366140), an intercalating agent with anti-cancer activity, inhibits the activity of topoisomerases 1 and 2. Pyrazoloacridine (NSC 366140) exhibits an IC50 of 1.25 μM in K562 myeloid leukemia cells for 24 h treatment[1][2].
Pyrazoloacridine (NSC 366140, PD 115934) exhibits IC50 values of 10.7 μM and 4.5 μM for oxic and hypoxic HCT-8 cells[1].Pyrazoloacridine (NSC 366140, 2-4 μM) abolishes the catalytic activity of both topo I and topo II in vitro[2].Pyrazoloacridine (NSC 366140) displays activity against cisplatin- and paclitaxel-resistant ovarian cancer[2].Pyrazoloacridine (NSC 366140) has been shown to cause delayed DNA fragmentation in MCF-7 breast cancer cells[2].Pyrazoloacridine (NSC 366140) induces apoptosis in P53-deficient Hep 3B human hepatoma cells[2]. Cell Cytotoxicity Assay[2] Cell Line: K562 Myeloid Leukemia Cells.
[1]. J S Sebolt, et al. Pyrazoloacridines, a new class of anticancer agents with selectivity against solid tumors in vitro. Cancer Res. 1987 Aug 15;47(16):4299-304. [2]. A A Adjei, et al. Effect of pyrazoloacridine (NSC 366140) on DNA topoisomerases I and II. Clin Cancer Res. 1998 Mar;4(3):683-91.
| Cas No. | 99009-20-8 | SDF | |
| 别名 | NSC366140无结构图,NSC 366140; PD 115934 | ||
| Canonical SMILES | O=[N+](C1=CC=C2C3=C1NC4=CC=C(OC)C=C4C3=NN2CCCN(C)C)[O-] | ||
| 分子式 | C19H21N5O3 | 分子量 | 367.4 |
| 溶解度 | 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 | 2.7218 mL | 13.6091 mL | 27.2183 mL |
| 5 mM | 0.5444 mL | 2.7218 mL | 5.4437 mL |
| 10 mM | 0.2722 mL | 1.3609 mL | 2.7218 mL |
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| 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 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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工作液浓度： mg/ml；
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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。
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Current status of Pyrazoloacridine as an anticancer agent
Invest New Drugs 1999;17(1):43-8.PMID:10555121DOI:10.1023/a:1006242321596.
Pyrazoloacridine (PZA) is the first of a new class of rationally synthesized acridine derivatives to undergo clinical testing as an anticancer agent. Recent studies suggest that PZA might be a dual inhibitor of DNA topoisomerase I and DNA topoisomerase II that exerts its effects by diminishing the formation of topoisomerase-DNA adducts. Consistent with this unique mechanism of action, PZA exhibits broad spectrum antitumor activity in preclinical models in vivo. In addition, this agent displays several unique properties including solid tumor selectivity, activity against hypoxic cells, and cytotoxicity in noncycling cells. PZA also retains full activity against cells that are resistant to other agents on the basis of overexpression of P-glycoprotein or the multidrug resistance-associated protein (MRP). PZA has been studied in phase I trials in adults and children, and is currently undergoing broad phase II trials in a number of tumor types. No significant anti-tumor activity has been seen in gastrointestinal malignancies and prostate cancer. Results from ongoing or recently completed trials are awaited before the utility of this agent in our current armamentarium can be defined. Because of its unique properties, combination studies with other antineoplastic agents are warranted.
Phase I/II trial of Pyrazoloacridine and carboplatin in patients with recurrent glioma: a North Central Cancer Treatment Group trial
Invest New Drugs 2005 Oct;23(5):495-503.PMID:16133802DOI:10.1007/s10637-005-2910-4.
Purpose: Novel therapeutic agents in the treatment of recurrent gliomas are urgently needed. Pyrazoloacridine (PZA), a rationally synthesized acridine derivative, has shown promising antitumor activity against glioma lines in combination with platinum compounds. This phase I/II trial of the PZA/carboplatin combination in recurrent glioma patients consisted of two phase I studies (studies 1 and 2) and a phase II trial (study 3). The objectives of studies 1 and 2 were to (a) assess the safety and toxicity and to establish the phase II dose of the Pyrazoloacridine/carboplatin combination for recurrent glioma patients on P450 inducing anticonvulsants, and (b) to confirm the phase II dose for patients not on P450 inducing anticonvulsants. The primary objectives of study 3 were to determine the efficacy of the Pyrazoloacridine/carboplatin combination in patients with recurrent gliomas, to further assess the toxicity of the combination, and to evaluate the impact of enzyme-inducing anticonvulsants on the Pyrazoloacridine metabolism. Experimental design: Both carboplatin and Pyrazoloacridine were administered intravenously every 28 days. Treatment was continued until unacceptable toxicity, tumor progression or patient withdrawal. Results: 14 patients were treated in the two phase I studies and 32 patients in the phase II trial. The phase II dose of the combination was PZA 400 mg/m(2) and carboplatin AUC of 5 every 28 days. Neutropenia (4 patients) and dyspnea (1 patient) was the dose limiting toxicity in the phase I studies. In the phase II trial, the most frequent toxicity was myelosuppression with grade 3 and 4 hematologic adverse events being observed in 22 and 19% of the patients, respectively. The antitumor activity of this regimen was limited; the response rate in the phase II trial was 0%, (95% CI:0-11%) while 12 of the 32 patients (38%) had stable disease with a median duration of 2 months. The percentage of phase II patients who were progression free at three months was 22% and at six months was 16%. Median survival from study entry was 5.0 months for phase I patients and 5.8 months for phase II patients. Pharmacokinetic analysis performed in 8 phase I patients demonstrated no significant impact of the enzyme-inducing anticonvulsants on the pharmacokinetics of Pyrazoloacridine. Conclusions: The phase II dose of the Pyrazoloacridine/carboplatin combination is Pyrazoloacridine 400 mg/m(2) in combination with carboplatin AUC of 5. Antitumor activity in patients with recurrent gliomas was limited. Initial disease stabilization occurred in approximately 38% of the patients, with median duration of 2 months. Enzyme-inducing anticonvulsants did not affect the Pyrazoloacridine metabolism.
Phase II trial of Pyrazoloacridine (NSC#366140) in patients with metastatic breast cancer
Invest New Drugs 2011 Apr;29(2):347-51.PMID:19844661DOI:10.1007/s10637-009-9338-1.
Purpose: Pyrazoloacridine (PZA) is an investigational nucleic acid binding agent that inhibits the activity of topoisomerases 1 and 2. We conducted a phase II clinical study to determine the efficacy and toxicities of PZA in patients with metastatic breast cancer (MBC). Experimental design: In this phase II multicenter study, patients who were treated with no more than one prior chemotherapy for MBC were treated with 750 mg/m² of PZA given as a 3-hour intravenous infusion every 3 weeks. Treatment cycles were continued until disease progression or unacceptable toxicities. The study was designed to distinguish between a response rate of < 15% vs > 30% (alpha = 0.10, beta = 0.10) using Simons optimal 2-stage design. At least 2 responses were required in the first 12 patients in the 1st stage and 6 of 35 in the 2nd stage to recommend the agent for further study. Results: Two patients in the first stage had a response allowing accrual to second stage. A total of 15 patients (out of 35 planned) were treated on the study prior to premature closure. Three patients had a partial response (20%) lasting 4.5-6 months. Two patients had stable disease for 3 and 5 months. The dose limiting toxicity was granulocytopenia with ten patients requiring dose reduction or dose delay for grade 4 neutropenia. Other grade 3 and 4 toxicities include vomiting (n = 2), nausea (n = 2), neurotoxicity (n = 1), fatigue (n = 1), anemia (n = 1), dyspnea 9n = 1) and renal (n = 1). Conclusions: Pyrazoloacridine demonstrated modest activity in patients with metastatic breast cancer.
Pharmacokinetics of Pyrazoloacridine in the rhesus monkey
Cancer Res 1991 Oct 15;51(20):5467-70.PMID:1913666doi
Pyrazoloacridine is a rationally synthesized acridine derivative with in vitro activity against solid tumor cell lines, noncycling and hypoxic cells, and tumor cell lines that exhibit the multidrug resistance phenotype. The pharmacokinetic behavior of Pyrazoloacridine after a 1- or 24-h i.v. infusion was studied in 5 rhesus monkeys that received a total of 10 courses of Pyrazoloacridine at 300 or 600 mg/m2. Pyrazoloacridine levels in plasma and cerebrospinal fluid were measured by high-pressure liquid chromatography. For 1-h infusions, the plasma disappearance was biexponential with a t 1/2 alpha of 31 min and t 1/2 beta of 11 h. The mean volume of distribution at steady state was 1380 liters/m2. The clearance was 1660 ml/min/m2. For the 300 mg/m2 dose, the mean area under the concentration-time curve was 759 microM.min, and the mean peak concentration was 1.3 microM. For the 600 mg/m2 dose, the area under the concentration-time curve was 1330 microM.min, and the peak concentration was 2.5 microM. The steady-state plasma concentrations during the 24-h continuous infusions were 0.27 microM for the 300 mg/m2 dose and 0.45 microM for the 600 mg/m2 dose. The mean clearance calculated from these steady-state concentrations was 2420 ml/min/m2. Cerebrospinal fluid levels were less than 0.1 microM for all doses and schedules. There was no evidence of toxicity at any dose or schedule. These results contrast strikingly with those obtained in mice and dogs in which, despite a more rapid clearance of Pyrazoloacridine, significant toxicities were observed at doses that were nontoxic in the monkey. These interspecies differences in the pharmacokinetic and pharmacodynamic behavior of Pyrazoloacridine have important implications for the design of Phase I trials in humans.
Phase II trial of Pyrazoloacridine in advanced non-small cell carcinoma of the lung--a Kansas Cancer Institute and Thompson Cancer Survival Center Study
Invest New Drugs 2002 Aug;20(3):339-42.PMID:12201497DOI:10.1023/a:1016293527755.
Background: More active agents are needed in the treatment of metastatic non-small cell lung cancer. Pyrazoloacridine (PZA) is a 9-methoxy acridine compound containing a reducible 5-nitro substituent. Although the mechanism of action of PZA is unknown, the acridine compounds are known to cause cytotoxicity by interaction with DNA and RNA. Methods: Eighteen patients with metastatic non-small cell lung carcinoma were treated with Pyrazoloacridine. Pyrazoloacridine was administered as a three-hour infusion at 750 mg/M2 every 21 days. Results: There were no objective responses. One patient maintained stable disease for 20 months. Median survival was 4.8 months. The primary toxicity was granulocytopenia with 5 patients experiencing severe infections. Conclusions: Pyrazoloacridine has no demonstrable activity in patients with metastatic non-small cell carcinoma of the lung when given at this dose and schedule.