Fotemustine (S10036)
(Synonyms: 福莫司汀) 目录号 : GC32827Fotemustine是一种DNA烷化剂(DNAalkylator),具有抗肿瘤作用。
Cas No.:92118-27-9
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Fotemustine is a DNA-alkylating agent, with antitumor activity.
Fotemustine is a DNA-alkylating agent. Fotemustine (800 μM) decreases GSH and intracellular GSSG levels but increases the extracellular GSSG-levels rapidly in isolated rat hepatocytes[1]. Fotemustine shows inhibitory effect on several tumor cell lines, with IC50s ranging form 0.05 to 0.18 mM[2].
[1]. Brakenhoff JP, et al. Molecular mechanisms of toxic effects of fotemustine in rat hepatocytes and subcellular rat liver fractions. Carcinogenesis. 1996 Apr;17(4):715-24. [2]. Merlin JL, et al. Enhancement of fotemustine (Muphoran) cytotoxicity by amifostine in malignant melanoma cell lines. Anticancer Drugs. 2002 Feb;13(2):141-7.
Cas No. | 92118-27-9 | SDF | |
别名 | 福莫司汀 | ||
Canonical SMILES | CC(P(OCC)(OCC)=O)NC(N(CCCl)N=O)=O | ||
分子式 | C9H19ClN3O5P | 分子量 | 315.69 |
溶解度 | DMSO : ≥ 3.2 mg/mL (10.14 mM) | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg | |
1 mM | 3.1677 mL | 15.8383 mL | 31.6766 mL |
5 mM | 0.6335 mL | 3.1677 mL | 6.3353 mL |
10 mM | 0.3168 mL | 1.5838 mL | 3.1677 mL |
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Enhancement of Fotemustine (Muphoran) cytotoxicity by amifostine in malignant melanoma cell lines
Anticancer Drugs 2002 Feb;13(2):141-7.PMID:11901306DOI:10.1097/00001813-200202000-00005.
Fotemustine (Muphoran, S10036), a nitrosourea derivative active in the treatment of malignant melanoma and primary brain tumors, was evaluated in combination with the free radicals cytoprotective agent amifostine (Ethyol, WR-2721) and its alkaline phosphatase (AP)-generated active metabolite WR-1065 in four human melanoma (RPMI-7950, SK-MEL2, SK-MEL5 and WM-115) and lung fibroblast (MRC-5) cell lines. No difference in AP activity was found among the melanoma cell lines, but AP was found to be significantly higher in MRC-5. For combination experiments, cell lines were first exposed to amifostine or WR-1065 for 15 min and then exposed to Fotemustine for two cell doubling times. Non-cytotoxic amifostine and WR-1065 concentrations used (0.2 and 0.6 and 0.1 and 0.3 mmol/l, respectively) were deduced from clinically achieved plasma values. Interactions were analyzed from the variations in IC(50) of Fotemustine induced by pre-exposure of the cells to amifostine or WR-1065. In all melanoma cell lines, amifostine enhanced the cytotoxic activity of Fotemustine as a significant decrease in IC(50) was observed. No significant difference was found between synergistic effects achieved with amifostine and WR-1065 given at half concentrations. No differential effect was found in the MRC-5 cell line as compared with the melanoma cell lines. Expression variation of O(6)-methylguanine methyltransferase was not found to be implicated in the interaction. The present results demonstrating that amifostine or its main active metabolite do not impair the cytotoxicity of Fotemustine justify an extensive clinical evaluation of this combination in metastatic melanoma.
Cytotoxicity and DNA damaging effects of a new nitrosourea, Fotemustine, diethyl- 1-(3-(2-chloroethyl)-3-nitrosoureido) ethylphosphonate-S10036
Anticancer Res 1989 Nov-Dec;9(6):1617-22.PMID:2627116doi
Fotemustine is a new chloroethylnitrosourea which has recently entered a Phase II clinical trial. Using standard cytotoxicity analyses, Fotemustine was shown to be preferentially active in two Mer- cell lines, human colon BE and human lung A427. Comparative cell kill in the Mer+ counterparts HT29 and A549 (respectively) was significantly lower. In a mouse cell line, P388, alkaline elution studies showed that Fotemustine caused fewer DNA strand breaks and total crosslinks (including DNA-protein) than either BCNU or MeCCNU at equivalent cytotoxic concentrations. In addition, the removal of DNA damage caused by Fotemustine was more rapid than of damage, three times as much Fotemustine was required. These data suggest that the cytotoxic mechanism of Fotemustine, although subject to the same repair mechanisms as other nitrosoureas, may not be entirely dependent upon DNA as the sole drug target. The previously reported reduced mutagenicity of this agent may also be a function of the less extensive nucleic acid damage. The encouraging early clinical trial results with this drug may reflect its improved pharmacokinetics and bioavailability, rather than any significant modification in its cellular pharmacology when compared to other nitrosoureas.
Renal effects of S10036 in man
Cancer Chemother Pharmacol 1990;26(6):467-8.PMID:2225319DOI:10.1007/BF02994102.
The renal hemodynamic and tubular effects of S10036 (Fotemustine) were evaluated in seven patients with advanced malignancy. Initial evaluation carried out prior to treatment and repeated 1 day after the first Fotemustine infusion and 7 days after the second included clinical, haematological parameters, liver-function tests, and determination of the glomerular filtration rate, renal blood flow and enzymuria. The glomerular filtration rate was 108 +/- 3.7 ml/min before treatment and remained stable after the first (117 +/- 5 ml/min) and second (124 +/- 6 ml/min) Fotemustine infusions. Renal blood flow and urinary beta 2-microglobulin and N'-acetylglucosaminidase excretion were also not modified by Fotemustine administration. We conclude that Fotemustine does not acutely alter renal haemodynamics, nor does it have direct tubular toxicity.
Antitumor activity of the novel nitrosourea S10036 in rodent tumors
Anticancer Res 1988 Nov-Dec;8(6):1351-4.PMID:3064716doi
The activity of the novel anticancer agent diethyl 1-3-(chloroethyl)-3-nitrosoureido ethyl phosphonate (S10036) was investigated on several rodent tumors. S10036 showed a good efficacy, comparable to that of the anticancer agent BCNU, against i.p transplanted P388 and L1210 leukemias. S10036 was very effective against the primary tumor and metastases of i.m transplanted M5076 reticular cell sarcoma of the mouse and against subline A of the Walker carcinoma of the rat. It was inactive against rodent tumors resistant to BCNU such as L1210/BCNU, ICIG-Ci4 murine fibrosarcoma and the Walker carcinoma subline B in the rat.