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Benzarubicin (N-benzyladriamycin-14-valerate; AD 198) exhibits unique combined functional characteristics that make it therapeutically superior to conventional anthracyclines, such as doxorubicin and daunorubicin.  The combined N-benzyl and 14-O-acyl substitutions increase lipophilicity and cell penetration, but restrict cellular uptake of drug to the cytoplasm, the principal site of action for benzarubicin.  The valerate group, in combination with portions of the chromophore ring structure, produces a three-dimensional structure that shows a striking similarity to diacyglycerol, an endogenous binding molecule for the C1b regulatory domain of the protein kinase C family of signaling enzymes.  Benzarubicin targets the PKC-delta isoform in a variety of proliferating tumor cell lines to trigger rapid apoptotic cell death utilizing novel mitochondrial pathway. Due to both its structure and mechanism of action, benzarubicin circum­vents multiple mechanisms of cellular drug resistance, including the increased expression of the multidrug transport proteins P-glycoprotein and MRP-1, anti-apoptotic proteins Bcl-2, Bcl-XL, and proliferative signaling proteins NF-kB and Bcr-Abl kinase.

In addition to its principal mechanism of action, benzarubicin also possesses potential multifunctional antitumor activity through ester hydrolysis of the 14-O-valerate sidechain to yield N-benzyladriamycin (AD 288).  AD 288 possesses antitumor potency comparable to benzarubicin, but through catalytic inhibition of topoisomerase II rather than PKC activation.

Benzarubicin is both non-cardiotoxic when administered alone and cardioprotective against both drug- and ischemia-induced damage through PKC-epsilon-mediated protection of myocardial cells against mitochondrial depolarization and irreversible loss of myocardial function.  In vivo rodent studies with benzarubicin have demonstrated greater systemic safety than doxorubicin, with no detectable pulmonary or hepatic toxicity at its maxi­mum tolerated dose.

Benzarubicin is currently being developed by Paradox Pharmaceuticals as a veterinary antitumor agent for the treatment of metastatic canine and feline tumors for which anthracycline-based therapy is currently indicated or has failed to achieve durable remission.  Pilot multicenter phase I trials against stage III/IV canine lymphoma have indicated that benzarubicin is generally well tolerated and demonstrates efficacy against previously untreated malignancies.

Benzarubicin