Development and antitumor activity of a BCL-2 targeted single-stranded DNA oligonucleotide.
PNT100 is a 24-base, chemically unmodified DNA oligonucleotide sequence that is complementary to a region upstream of the BCL-2 gene. Exposure of tumor cells to PNT100 results in suppression of proliferation and cell death by a process called DNA interference. PNT2258 is PNT100 that is encapsulated in protective amphoteric liposomes developed to efficiently encapsulate the PNT100 oligonucleotide, provide enhanced serum stability, optimized pharmacokinetic properties and antitumor activity of the nanoparticle both in vivo and in vitro. PNT2258 demonstrates broad antitumor activity against BCL-2-driven WSU-DLCL2 lymphoma, highly resistant A375 melanoma, PC-3 prostate, and Daudi-Burkitt's lymphoma xenografts. The sequence specificity of PNT100 was demonstrated against three control sequences (scrambled, mismatched, and reverse complement) all encapsulated in a lipid formulation with identical particle characteristics, and control sequences did not demonstrate antiproliferative activity in vivo or in vitro. PNT2258 is currently undergoing clinical testing to evaluate safety and antitumor activity in patients with recurrent or refractory non-Hodgkin's lymphoma and additional studies are planned.
ProNAi Therapeutics, Inc., Plymouth, MI, USA, wrodrigueza@pronai.com.
Wendi V
WV
Rodrigueza
Michael J
MJ
Woolliscroft
Abdul-Shukkur
AS
Ebrahim
Robert
R
Forgey
Patrick J
PJ
McGovren
Gerold
G
Endert
Andreas
A
Wagner
Danielle
D
Holewa
Amro
A
Aboukameel
Richard D
RD
Gill
Charles L
CL
Bisgaier
Richard A
RA
Messmann
Christopher E
CE
Whitehead
Elzbieta
E
Izbicka
Robert
R
Streeper
Michael C
MC
Wick
Gabriela
G
Stiegler
C A
CA
Stein
David
D
Monsma
Craig
C
Webb
Mina P
MP
Sooch
Steffen
S
Panzner
Ramzi
R
Mohammad
Neal C
NC
Goodwin
Ayad
A
Al-Katib
D024506:5' Flanking Region / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016373:DNA, Antisense / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D004277:DNA, Single-Stranded / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D004339:Drug Compounding; D004355:Drug Stability; D005260:Female; D020868:Gene Silencing / Q000187:drug effects*; D008081:Liposomes; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D014677:Pharmaceutical Vehicles; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011897:Random Allocation; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D016373:DNA, Antisense; D004277:DNA, Single-Stranded; D008081:Liposomes; D009838:Oligodeoxyribonucleotides; C000588986:PNT100; D014677:Pharmaceutical Vehicles; D019253:Proto-Oncogene Proteins c-bcl-2