Pyroxamide (NSC 696085)

Pyroxamide causes the accumulation of acetylated core histones in MEL cells cultured with the agent. Pyroxamide, at micromolar concentrations, induces terminal differentiation and inhibits proliferation of murine erythroleukemia(MEL) cells. Pyroxamide (1.25-20 mM) causes dose-dependent inhibition of growth by cell cycle arrest of prostate carcinoma (LNCaP), neuroblastoma (KCN-69n), and bladder carcinoma (T24) cells in culture, with similar efficacy in all of the cell lines. ^[1] A concentration of 1.25-20.0 μM Pyroxamide causes a dose-dependent decrease in viable cell number and an increase in percentage of dead cells over time in two Rhabdomyosarcoma cell lines, RD (embryonal ) and RH30B (alveolar). Accumulation of acetylated histones and induction of p21/WAF1 expression are obersevd in cells exposed to Pyroxamide. ^[2] Pyroxamide shows a dose- and time-dependent proliferation inhibition, induction of apoptosis and histone H4 hyperacetylation in three B-cell precursor (BCP)-acute lymphoblastic leukemia (ALL) cell lines (Reh, Nalm6, Z33). The calculated IC50 after 96 hours of Pyroxamide incubation are 2-6 μM. ^[3]

1-2 × 10⁵ cells/mL MEL Ds19/Sc9 cells are cultured with increasing concentrations of Pyroxamide (0.625-8 μM) for 5 days, at which time the Benzidine positivity is determined as an indicator of terminal differentiation. MEL cell density is measured using a Coulter counter and viability is assessed by trypan blue exclusion.

Administration of 100 or 200 mg/kg of Pyroxamide daily for 21 days causes significant, dose-dependent suppression of the growth of the tumor xenograft. A dose of 300 mg/kg Pyroxamide is lethal to all of the mice in the treatment group within 1 week. After in vivo administration of Pyroxamide, accumulation of acetylated histones and a dose-dependent increase in the expression of p21/WAF1 protein level are observed. ^[1]