Preclinical development of a new leukaemia drug, PENAO
2007; American Association for Cancer Research; Volume: 67; Linguagem: Inglês
ISSN
1538-7445
AutoresPierre J. Dilda, Wimali Weerakoon, Amanda Philp, John Allen, Richard B. Lock, Philip J. Hogg,
Tópico(s)Biotin and Related Studies
Resumo5593 Arsenic trioxide is a trivalent arsenical that selectively kills acute promyelocytic leukaemia (APL) cells. It is also showing promise for the treatment of myelodysplastic syndrome, a disease for which no standard treatment currently exists. Side effects of arsenic trioxide include QTc prolongation, APL differentiation syndrome, peripheral neuropathies, hepatic dysfunction and gastrointestinal reactions. We have made a water-soluble derivative of arsenic trioxide in an attempt to blunt its side-effects. Eliminating the lipid solubility of arsenic trioxide should reduce its penetration into tissues and help restrict the drug mostly to the intravascular compartment where it acts. Phenylarsenoxide was conjugated to penicillamine to produce PENAO (4-(N-(S-penicillamine acetyl)amino)-phenylarsenoxide). PENAO is a mitochondrial poison. It cross-links closely spaced cysteine thiols on the matrix face of the inner-membrane transporter, adenine nucleotide translocase (ANT). ANT exchanges matrix ATP for cytosolic ADP across the inner-mitochondrial membrane and is the key component of the mitochondrial permeability transition pore. Inactivation of ANT by PENAO triggers mitochondrial permeability transition which results in proliferation arrest and apoptosis of cultured cells. PENAO cellular levels are controlled by export via the ATP- and glutathione-dependent multidrug resistance-associated proteins 1 and 2. PENAO was tested for anti-proliferative and cytotoxic activity on numerous carcinoma and primary cell lines and was found to be selective for APL cells and for some acute lymphoblastic leukaemia (ALL) cells derived from patients. PENAO is equivalent to arsenic trioxide in its effects on APL cells (NB4) and more efficacious than dexamethasone on some ALL cells. PENAO is reasonably well tolerated in mice with a MTD of ≈1mg/kg/day. Plasma PENAO levels peak at ≈15 μM following a single intraperitoneal administration of 1.5 mg/kg PENAO. Studies of the efficacy of PENAO in mouse models of human leukaemia are underway.
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