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(Synonyms: NCI 329680; ZINC01574758) 目录号 : GC33119

Hepsulfam (NCI 329680) (NCI 329680; ZINC01574758) 是一种抗癌剂,在一组不同的肿瘤中显示出优异的抗白血病活性,中位 IC50 为 0.91 μg/mL。

Hepsulfam (NCI 329680) Chemical Structure

Cas No.:96892-57-8

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实验参考方法

Cell experiment:

HL-60 or K562 leukemia cells (1x106/mL) are treated with various concentrations of hepsulfam for 2, 3,6, 9, or 12 h at 37°C. The concentration of DMSO in either control or treated cells is never greater than 2% (v/v). Following drug exposure, the cells are ished by centrifugation in RPMI 1640 medium and resuspended in fresh medium. Following this ish, cells are either assayed immediately for DNA damage by alkaline elution or incubated at 37°C for various periods before assay. BE and HT-29 human colon carcinoma cells are processed for alkaline elution analysis or cytotoxicity assays[2].

References:

[1]. Berger DP, et al. Preclinical activity of hepsulfam and busulfan in solid human tumor xenografts and human bone marrow. Anticancer Drugs. 1992 Oct;3(5):531-9.
[2]. Pacheco DY, et al. Mechanisms of toxicity of hepsulfam in human tumor cell lines. Cancer Res. 1990 Dec 1;50(23):7555-8.

产品描述

Hepsulfam (NCI 329680; ZINC01574758) is a anticancer agent that shows excellent antileukemic activity with an median IC50 of 0.91 μg/mL in a panel of different tumors.

At a concentration of 1.0 μg/mL, hepsulfam is active in eight of 37 tumors (22%) in the clonogenic assay. Hepsulfam demonstrates a clear in vitro toxicity to human bone marrow cells (CFU-GM) from healthy donors. Evaluation of equitoxic concentrations in vitro reveals a higher activity of hepsulfam, especially in non-small cell lung cancer[1]. Hepsulfam is more toxic to L1210 leukemia cells than is busulfan, its structural homologue . Consistent with the difference in toxicity, hepsulfam induces DNA interstrand cross-links in L1210 mouse leukemia cells, whereas busulfan does not. Hepsulfam is more cytotoxic to two human leukemia cell lines (111-60 and K562) and to two human colon carcinoma cell lines (BE and HT-29) than is busulfan. As in 11210 cells, hepsulfam induces a higher level of DNA interstrand cross-links than busulfan. Hepsulfam is also more cytotoxic to the human leukemia cell lines when the concentrations are reduced 10-fold and the duration of drug exposure is increased to 12 h[2].

Hepsulfam demonstrates superior in vivo activity in a large cell lung cancer xenograft and a gastric carcinoma model. The preclinical activity of hepsulfam suggests a possible role of this compound in the treatment of solid human malignancies. However, the increased bone marrow toxicity of hepsulfam as compared with busulfan might be critical for further clinical application[1].

[1]. Berger DP, et al. Preclinical activity of hepsulfam and busulfan in solid human tumor xenografts and human bone marrow. Anticancer Drugs. 1992 Oct;3(5):531-9. [2]. Pacheco DY, et al. Mechanisms of toxicity of hepsulfam in human tumor cell lines. Cancer Res. 1990 Dec 1;50(23):7555-8.

Chemical Properties

Cas No. 96892-57-8 SDF
别名 NCI 329680; ZINC01574758
Canonical SMILES O=S(OCCCCCCCOS(=O)(N)=O)(N)=O
分子式 C7H18N2O6S2 分子量 290.36
溶解度 Soluble in DMSO 储存条件 Store at -20°C
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1 mM 3.444 mL 17.22 mL 34.44 mL
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10 mM 0.3444 mL 1.722 mL 3.444 mL
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Research Update

Phase I and pharmacokinetic study of Hepsulfam (NSC 329680)

Cancer Res 1991 Nov 1;51(21):5781-5.PMID:1933848doi

Hepsulfam (NSC 329680), a bifunctional alkylating agent structurally related to busulfan, has entered clinical trial based on its broader preclinical antitumor activity compared with that of busulfan and its i.v. formulation which may circumvent the many problems arising from the p.o. administration of busulfan, such as significant individual differences in bioavailability. In this Phase I study, 53 patients received 95 courses of Hepsulfam at doses ranging from 30 to 480 mg/m2 administered i.v. over 30 min every 28 days. Hematological toxicity was dose limiting. Leukopenia and thrombocytopenia were dose related, delayed in onset, and sustained for long durations. Toxicity was cumulative in most patients receiving more than one course. This pattern of myelosuppression suggests that Hepsulfam is cytotoxic to hematopoietic stem cells. Although hematological toxicity was not particularly severe during most courses, its lengthly duration precluded the prompt administration of subsequent courses. Minimal nonhematological effects were observed. Pharmacokinetic studies revealed that the clearance rate of Hepsulfam is linear over the dose range studied and that its plasma disposition is biphasic with mean alpha and beta half-lives of 19 +/- 18 (SE) min and 337 +/- 248 (SE) min, respectively. The area under the plasma clearance curve correlated with the percentage of change in WBC using a sigmoidal Emax model and with the duration of thrombocytopenia in patients with hematological toxicity. Based on the protracted duration of the toxicity of multiple doses that were greater than 210 mg/m2, the recommended starting dose for Phase II trials is 210 mg/m2. However, these trials should be pursued with caution because of the protracted nature of Hepsulfam's myelosuppression. Because Hepsulfam produced minimal nonhematological toxicity, substantial dose escalation above 480 mg/m2 may be possible with hematopoietic stem cell support.

Mechanisms of toxicity of Hepsulfam in human tumor cell lines

Cancer Res 1990 Dec 1;50(23):7555-8.PMID:2253204doi

1,7-Heptanediol disulfamate (Hepsulfam, NSC 329680) is a new anti-cancer agent which is currently undergoing phase I clinical trials. The mechanism of action of this compound is not clear at this time. We have recently shown that Hepsulfam was more toxic to L1210 leukemia cells than was busulfan. Consistent with the difference in toxicity, we found that Hepsulfam induced DNA interstrand cross-links in L1210 mouse leukemia cells, whereas busulfan did not. In the present study, we have found that Hepsulfam was more cytotoxic to two human leukemia cell lines (HL-60 and K562) and to two human colon carcinoma cell lines (BE and HT-29) than was busulfan. As in L1210 cells, Hepsulfam induced a higher level of DNA interstrand cross-links than busulfan. Both compounds induced DNA-protein cross-links. Hepsulfam was also more cytotoxic to the human leukemia cell lines when the concentrations were reduced 10-fold and the duration of drug exposure was increased to 12-h This more accurately reflects the drug exposures that human leukemia cells may encounter in vivo. Under these 12-h drug exposures, Hepsulfam was still able to form DNA interstrand and DNA-protein cross-links, whereas busulfan was only able to form DNA-protein cross-links. These results show that busulfan and Hepsulfam react with DNA differently and that Hepsulfam is a more potent cytotoxic agent.

In vitro cytotoxicity of Hepsulfam against human tumor cell lines and primary human tumor colony forming units

Stem Cells 1993 Jan;11(1):62-9.PMID:8457783DOI:10.1002/stem.5530110111.

Hepsulfam (sulfamic acid 1,7-heptanediyl ester, NSC 329680) is an alkylating agent currently in Phase I clinical trials. Hepsulfam was developed as an analog of busulfan, an alkylating agent that is used to treat patients with chronic myelogenous leukemia and for marrow ablation prior to bone marrow transplantation. The objective of this study was to identify the spectrum of human tumor cells that were sensitive to Hepsulfam. The following three cytotoxicity assays were employed to evaluate the in vitro cytotoxic potential of Hepsulfam: 1) primary human tumors were exposed to three levels of Hepsulfam for a one hour or continuous exposure, and growth in soft agar was determined; 2) human non-tumor cells and tumor cell lines were compared in an assay that measured the conversion of 14C-glucose to 14CO2 as an index of viability; and 3) the toxicity of Hepsulfam to hematopoietic progenitor cells was determined in a progenitor cell colony forming assay. Cytotoxicity was not observed for human tumor cells following one hour Hepsulfam exposures; in contrast, marked dose-dependent cytotoxicity was observed with continuous exposures. In human tumor cell lines, the cytotoxicity of Hepsulfam was compared directly with busulfan at equimolar concentrations. Hepsulfam was more cytotoxic than busulfan in all cell lines tested. Cytotoxic activity was seen in lung, melanoma, kidney, breast, colon, ovary and brain tumor cells. These results, along with the information obtained from Phase I trials, will facilitate selection of patients who could receive this agent in Phase II efficacy trials.

Hepsulfam sensitivity in human breast cancer cell lines: the role of glutathione and glutathione S-transferase in resistance

Cancer Res 1992 Mar 15;52(6):1416-21.PMID:1540950doi

Hepsulfam (NSC 329680, 1,7-heptanediol disulfamate) is an alkylating agent that showed excellent activity against mouse and human mammary carcinoma in preclinical studies. We therefore studied the cytotoxicity of this drug in six human breast cancer cell lines (AdrRMCF7, WTMCF7, Hs578T, MDA-MB-231, T47D, and MDA-MB-468). Clonogenic assays of these cell lines showed a range of sensitivity with the 90% inhibitory concentration ranging from 3.1 microM Hepsulfam (MDA-MB-468) to 32.3 microM Hepsulfam (AdrRMCF7) after 24-h exposure to the drug. To evaluate possible mechanisms responsible for this observed variation in sensitivity to Hepsulfam, we have studied glutathione S-transferase (GST) activity and glutathione (GSH) in these cell lines. Total cytoplasmic GST activity correlated with sensitivity; the most sensitive cell lines had the lowest GST activity, while the two most resistant cell lines, AdrRMCF7 and Hs578T, had the highest GST levels of the six cell lines. Western blot analysis showed that the only detectable isoenzyme was GST-pi. The amount of GST-pi isoform correlated with Hepsulfam sensitivity in the three most resistant cell lines and was undetectable in the three most sensitive cell lines. Cellular concentrations of GSH did not correlate with Hepsulfam sensitivity. However, GSH depletion with buthionine sulfoximine increased sensitivity to Hepsulfam in a dose-dependent fashion in all six cell lines. Evaluation by mass spectrometry revealed that glutathione can form conjugates with Hepsulfam. We conclude that the GST/GSH detoxication system plays a role in the sensitivity of these breast cancer cell lines to Hepsulfam.

Hepsulfam distribution in blood, plasma and cerebrospinal fluid of baboons

Invest New Drugs 1995;13(1):33-6.PMID:7499105DOI:10.1007/BF02614217.

The alkylating agent Hepsulfam (Sulfamic acid 1,7-heptanediyl ester, NSC 329680) was developed as a more hydrophilic analog of busulfan. The objective of this study was to determine partitioning of Hepsulfam between blood, plasma, and cerebrospinal fluid (CSF) in two female baboons following intravenous administration. Hepsulfam was administered at 11 mg/kg, and blood and CSF levels were determined by gas chromatography with electron capture detection. Blood levels were fairly constant between animals (17-25 and 20-23 micrograms/ml) for six hours after administration, following peak levels of 43 and 33 micrograms/ml, respectively, for the two animals. Peak plasma levels of 35 and 36 micrograms/ml were achieved, and initial plasma half-lives in baboons were similar to those seen in other species, with a t1/2 alpha of 1 h. The plasma terminal half life of 0.2 h, estimated from limited sampling times, was shorter in baboons than in mice, dogs, or humans. Baboon CSF levels decreased from 1.7 to 0.3 micrograms/ml during 6 h post infusion, and peak concentrations in CSF lagged behind plasma levels. CSF/plasma ratios ranged from 0.33 to 0.62 in one animal, whereas ratios of 0.2-0.25 were maintained in the other animal during the same period. Results from this study indicate Hepsulfam will enter the CSF following intravenous administration, and the CSF/plasma ratios are lower than those obtained following oral busulfan administration.