Molecule

In Vitro

Methazolastone causes formation of DNA alkali-labile sites which are present in similar amounts and repaired at a similar rate in L-1210 and L-1210/BCNU. In L-1210 but not in L-1210/BCNU methazolastone induces an arrest of cells in SL-G2-M phases. Methazolastone induces a similar amount of DNA ALS which is also repaired at a similar rate in L-1210 and L-1210/BCNU cell lines. Methazolastone induces a similar amount of DNA ALS which is also repaired at a similar rate in L-1210 and L-1210/BCNU cell lines. ^[1] Methazolastone sensitivity of both chemo-sensitive and resistant cells (D54-R and U87-R) is enhanced significantly under hyperoxia. Both Methazolastone and hyperoxia are associated with increased phosphorylation of ERK p44/42 MAPK (Erk1/2), but to a lesser extent in D54-R cells, suggesting that Erk1/2 activity may be involved in regulation of hyperoxia and Methazolastone-mediated cell death. Hyperoxia enhances Methazolastone toxicity in GBM cells by induction of apoptosis, possibly via MAPK-related pathways. ^[2] Methazolastone induces in monocytes the DNA damage response pathways ATM-Chk2 and ATR-Chk1 resulting in p53 activation. ^[3] Chronic Methazolastone exposure results in acquired Methazolastone-resistance and elevates miR-21 expression. ^[4] Methazolastone treatment triggers endoplasmic reticula (ER) stress with increased expression of GADD153 and GRP78 proteins, and deceases pro-caspase 12 protein. Methazolastone induces autophagy through mitochondrial damage- and ER stress-dependent mechanisms to protect glioma cells. ^[5]

In Vivo

After a daily i.p. dose of 40 mg/kg for 5 consecutive days (days 1-5 after tumor transplant), methazolastone increases life-span by 86% in L-1210 and 22% in L-1210/BCNU. In L-1210/BCNU no effect is seen after 100 μM or 200 μM treatment; only 400 μM methazolastone produced an accumulation of cells in premitotic phase but much less than in L-1210. In L-1210/BCNU the maximum accumulation of cells in SL-G2-M is, after 48 hours-72 hours, approximately 30% as compared to 23% in untreated cells. Cells accumulates in SL-G2-M occurred too when L- 1210 leukemia-bearing mice are treated i.v. with methazola stone (40 mg/kg). No such effect is seen on L-1210/BCNU cells from mice given the same drug dose. ^[1]

Clinical Trials

Methazolastone plus TPI 287 has entered in a phase II clinical trial in the treatment of melanoma.

Features

Methazolastone is a second-generation alkylating agent.