Disease relevance of Cystemustine

• Cystemustine induces redifferentiation of primary tumors and confers protection against secondary tumor growth in a melanoma murine model [1].
• Both healthy mice and tumor-bearing mice were given a single i.p. injection of cystemustine (20 mg/kg) 3 days after the onset of cachexia [2].
• Therefore, cystemustine-treated B16 melanoma tumors acquire a new Plp metabolism phenotype, a mechanism that could participate in tumor cell redifferentiation and/or survival [3].
• The lowest cystemustine toxicity was found near the middle of the active span of the rest-activity circadian cycle of mice [4].
• Phase II study of cystemustine in metastatic colorectal carcinoma. A trial of the EORTC Clinical Screening Group [5].

High impact information on Cystemustine

• Melanoma tumors acquire a new phospholipid metabolism phenotype under cystemustine as revealed by high-resolution magic angle spinning proton nuclear magnetic resonance spectroscopy of intact tumor samples [3].
• The data presented in this report indicate that cystemustine-treated cells or the administration of cystemustine provoke an important growth delay of primary melanoma tumors, together with an increase in cell pigmentation and cell morphology changes [1].
• In contrast, mucosal damage and a 17% reduction in small intestinal protein mass (P < 0.05) were evident in healthy mice treated with cystemustine, suggesting that the effects of chemotherapy on the small intestine in a state of cancer cachexia are not additive, which was an unexpected finding [2].
• Target organ toxicities (bone marrow, circulating blood cells, spleen, colon and duodenum) were studied following a single slightly lower dose of cystemustine [4].
• Cystemustine is a new nitrosourea with high anti-tumor activity and a short plasma half-life in mice [4].

Chemical compound and disease context of Cystemustine

• 27 patients with metastatic colorectal carcinoma were treated, every 2 weeks, with 60 mg/m2 cystemustine, a new chloro-2-ethyl nitrosourea derivative [5].
• We have shown that this compound is able to deplete AGT activity on M4Beu human melanoma cells and to enhance the antitumor power of CENU N'-[2-chloroethyl]-N-[2-(methylsulfonyl)ethyl]-N'-nitrosourea (cystemustine) towards the M4Beu melanoma grafted on nude mice [6].
• We evaluated the influence of AGAT activity inhibition by BNAG on the ability of two CENUs, 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and 3-(2-chloroethyl)-1-(2-methylsulphonyl)ethyl-3-nitrosourea (cystemustine), to induce an apoptotic response in two melanoma cell lines, M3 Dau (Mer ) and IPC 227F (Mer ) [7].

Biological context of Cystemustine

• Late survival rate varied from 4% in mice receiving a single dose of cystemustine (conventional lethal dose 50%) at 7 hours after light onset (HALO) up to 88% in mice treated at 15 or at 19 HALO [4].
• Circadian rhythm in toxic effects of cystemustine in mice: relevance for chronomodulated delivery [4].
• CONCLUSIONS: There was a clear linear relationship between the area under the blood drug concentration-time curve (AUC) and the dose of cystemustine (P < 0.001) [8].
• Pharmacokinetics analysis showed mono- or biphasic cystemustine blood disposition with a mean a half-life of 4 min and mean terminal half-life of 49 min [8].
• To investigate the toxicity of BNAG and cystemustine when administered simultaneously in mice, we compared the maximum tolerated dose and LD50 doses of cystemustine alone or in combination with 40 mg kg(-1) BNAG by the i.p. route [9].

Anatomical context of Cystemustine

• Leukocyte count nadir occurred 7 days after injection and was lowest following cystemustine at 7 HALO as compared to 13 or 19 HALO [4].
• Bone-marrow necrotic lesions were more pronounced 1 day after cystemustine at 7 HALO than after cystemustine at 19 HALO [4].
• The results show that 3 days after cystemustine treatment, these melanocytes had accumulated in phase G2 of the cell cycle [10].

Gene context of Cystemustine

• Previously, we have shown that O6-benzyl-N2-acetylguanosine (BNAG), an MGMT inhibitor, can be combined with cystemustine by intravenous administration, and increases the antitumour effect of cystemustine in resistant human melanoma [11].
• The concentration-dependent number of apoptotic cells assessed using a terminal deoxynucleotidyl transferase-mediated dUTP-fluorescein nick-end labelling (TUNEL) assay 72 h after BCNU or cystemustine treatment (0-400 microM for 2 h) was increased by prior AGAT depletion with BNAG pretreatment (300 microM for 4 h) in Mer cells [7].

Analytical, diagnostic and therapeutic context of Cystemustine

• Three days after cachexia began, healthy and tumor-bearing mice were given a single intraperitoneal injection of cystemustine (20 mg/kg) [12].
• This study included 39 patients (37 evaluable, of whom 30 patients with recurrent gliomas and 7 patients with gliomas untreated by radiotherapy); they were enrolled into a phase II trial using a new nitrosourea, cystemustine, administrated every 2 weeks at 60 mg/m2 as a 15 min-infusion [13].
• CASE PRESENTATION: We describe 5 cases, presenting with complete response with long-term disease-free survival of long-term remission of 14, 12, 9, 7 and 6 years after Cystemustine therapy alone [14].

References