Characterization of NVX-207, a novel betulinic acid-derived anti-cancer compound.
BACKGROUND
Development of betulinic acid derivatives for clinical use has been hampered by adverse pharmacological and physico-chemical characteristics of this class of compounds. We here present a novel semi-synthetic betulinic acid-derived drug candidate well suited for further clinical development.


METHODS
In vitro activity and mode of action of NVX-207 were determined using normal as well as cancer cell lines. Gene expression profiling was performed with Affymetrix U133 microarrays. NVX-207 binding partners were identified using a heterobifunctional chemical crosslinker system. Potential binding proteins were identified by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) analysis. Clinical studies were conducted in canine cancer patients suffering from spontaneously arising pre-treated tumours.


RESULTS
NVX-207 showed anti-tumour activity (mean IC(50) = 3.5 microM) against various human and canine cell lines. NVX-207-induced apoptosis was associated with activation of the intrinsic apoptotic pathway via cleavage of caspases -9, -3, -7 and of poly (ADP-ribose) polymerase (PARP). Global gene expression profiling demonstrated regulation of genes associated with lipid metabolism, most notably an upregulation of genes coding for insulin-induced gene 1 (Insig-1), low-density lipoprotein receptor (LDL-R) and of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA). NVX-207 bound to apolipoprotein A-I, a major regulator of lipid metabolism and cholesterol transport. A phase I/II study in dogs suffering from naturally occurring cancer receiving local treatment of NVX-207 (10 mg mL(-1)) showed excellent clinical responses including a complete remission in so far 5/5 treated animals.


CONCLUSIONS
NVX-207 is well tolerated and has significant anti-cancer activity in vitro and in vivo in dogs with treatment-resistant malignancies.
Willmann
M
M
Clinic for Internal Medicine and Infectious Diseases, University of Veterinary Medicine Vienna, Vienna, Austria.
Wacheck
V
V
Buckley
J
J
Nagy
K
K
Thalhammer
J
J
Paschke
R
R
Triche
T
T
Jansen
B
B
Selzer
E
E
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D045744:Cell Line, Tumor / Q000187:drug effects; D004285:Dogs; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D051379:Mice; D023421:Models, Animal; D053978:Pentacyclic Triterpenes; D011412:Propanolamines / Q000494:pharmacology*; D014315:Triterpenes / Q000494:pharmacology*; D000094062:Betulinic Acid
C000599178:2-amino-3-hydroxy-2-hydroxymethylpropyl 3-acetylbetulinoate; D016588:Anticarcinogenic Agents; D000972:Antineoplastic Agents, Phytogenic; D053978:Pentacyclic Triterpenes; D011412:Propanolamines; D014315:Triterpenes; D000094062:Betulinic Acid