Disease relevance of Hepsulfam

• However, thrombocytopenia of < 100 x 10(9) platelets/L was not shortened (persisted from day 12 to day 25), or less severe (nadir of 56 +/- 32 x 10(9) platelets/L on day 14; P = .7 compared with untreated hepsulfam animals) [1].
• Thus, both thrombocytopenia and neutropenia are eliminated by initiating daily PEG-rHuMGDF therapy on day 1 and subsequently adding daily rHu-GCSF after 1 week in the rhesus model of hepsulfam marrow suppression [1].
• Using a recently developed hepsulfam-induced pancytopenia model in rhesus macaques, we have studied the effects of recombinant human interleukin-6 (rhIL-6) and rhIL-3 on marrow regeneration [2].
• Mechanisms of toxicity of hepsulfam in human tumor cell lines [3].
• We have recently shown that hepsulfam was more toxic to L1210 leukemia cells than was busulfan [3].

High impact information on Hepsulfam

• In six hepsulfam-only control animals thrombocytopenia (platelet count < 100 x 10(9)/L) was observed between days 12 and 25 (nadir 39 +/- 20 x 10(9)/L on day 17), and neutropenia (absolute neutrophil count < 1 x 10(9)/L) occurred between days 8 and 30 (nadir 0.167 +/- 0.120 x 10(9)/L on day 15) [1].
• We have also isolated and identified 1-guanyl,7-hydroxyheptane, 1-guanyl,7-sulfamylheptane, and 1,7-bis(guanyl)heptane from in vitro reaction mixtures of hepsulfam and calf thymus DNA [4].
• Molecular pharmacology of hepsulfam, NSC 3296801: identification of alkylated nucleosides, alkylation site, and site of DNA cross-linking [4].
• We conclude that the GST/GSH detoxication system plays a role in the sensitivity of these breast cancer cell lines to hepsulfam [5].
• 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 [5].

Chemical compound and disease context of Hepsulfam

• Our results show that L1210 leukemia cells were 7-fold more sensitive to hepsulfam than busulfan [6].
• Comparative toxicity of fostriecin, hepsulfam and pyrazine diazohydroxide to human and murine hematopoietic progenitor cells in vitro [7].

Biological context of Hepsulfam

• PEG-rHuMGDF (2.5 micrograms/kg/d) injected subcutaneously into four animals from day 1 to day 22 following hepsulfam administration produced trough serum concentrations of 1.9 +/- 0.2 ng/mL and increased the platelet count twofold over basal prechemotherapy levels (856 +/- 594 x 10(9)/L v baseline of 416 +/- 88 x 10(9)/L; P = .01) [1].
• We conclude that the maximally tolerated dose when hepsulfam is given as a single dose every 35 days is 210 mg/m2, but that there is significant risk of cumulative hematological toxicity at this level [8].
• In the present study, we have compared the in vitro cytotoxicity of hepsulfam with that of busulfan and we also examined the ability of these compounds to induce DNA damage in the L1210 leukemia cell line [6].
• The median IC50 of hepsulfam and busulfan was determined as 0.93 and 3.31 micrograms/ml, respectively [9].

Anatomical context of Hepsulfam

• 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 [3].
• Murine CFU-e were also more sensitive to Hepsulfam than human CFU-e, with CFU-gm and BFU-e being similarly affected in both species [7].
• 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 [10].
• In vitro cytotoxicity of hepsulfam against human tumor cell lines and primary human tumor colony forming units [11].
• However, the increased bone marrow toxicity of hepsulfam as compared with busulfan might be critical for further clinical application.(ABSTRACT TRUNCATED AT 250 WORDS)[9]

Associations of Hepsulfam with other chemical compounds

• 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 [3].
• Evaluation by mass spectrometry revealed that glutathione can form conjugates with hepsulfam [5].
• The in vitro myelotoxic potentials of three investigational antitumor agents, Fostriecin, Hepsulfam and pyrazine diazohydroxide (PZDH), were evaluated utilizing clonogenic assays [7].
• The excision of hepsulfam-induced DNA adducts has been determined by treatment with homogeneous recombinant bacterial, rat and human 3-methyladenine DNA glycosylases and successive treatments by formamidopyrimidine-DNA glycosylase [12].

Gene context of Hepsulfam

• The mechanism of action of hepsulfam is not known and it has recently been entered into Phase I clinical trials by the National Cancer Institute. Waud et al. have recently shown that hepsulfam has good antitumor activity against mouse L1210 leukemia in vivo (Waud et al., Proc. Am. Assoc. Cancer Res., 29:333, 1988) [6].
• In addition, the cytotoxicity assay showed that E. coli mutant strains defective in the alkA gene or the uvrA gene were more sensitive to killing by hepsulfam than the wild type [12].
• This pattern of myelosuppression suggests that hepsulfam is cytotoxic to hematopoietic stem cells [13].
• Fostriecin (0.22-220 microM), Hepsulfam (0.34-340 microM) and PZDH (0.68-680 microM) inhibited myeloid (CFU-gm), erythroid (BFU-e, CFU-e) and megakaryocytic (CFU-meg) colony formation in a concentration-dependent manner [7].

Analytical, diagnostic and therapeutic context of Hepsulfam

• Plasma levels of hepsulfam were quantified by gas chromatography in 12 patients [8].
• 1,7-Heptanediol disulfamate (hepsulfam, NSC 329680) is a new anti-cancer agent which is currently undergoing phase I clinical trials [3].
• The recommended phase II dose of hepsulfam as a single 2-h intravenous infusion is 480 mg/m2, but this dose provided relatively little clinical benefit for patients with refractory leukemia [14].
• Hepsulfam demonstrated superior in vivo activity in a large cell lung cancer xenograft and a gastric carcinoma model [9].

References