1. Development and antitumor activity of a BCL-2 targeted single-stranded DNA oligonucleotide.
- Author
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Rodrigueza WV, Woolliscroft MJ, Ebrahim AS, Forgey R, McGovren PJ, Endert G, Wagner A, Holewa D, Aboukameel A, Gill RD, Bisgaier CL, Messmann RA, Whitehead CE, Izbicka E, Streeper R, Wick MC, Stiegler G, Stein CA, Monsma D, Webb C, Sooch MP, Panzner S, Mohammad R, Goodwin NC, and Al-Katib A
- Subjects
- 5' Flanking Region drug effects, Animals, Antineoplastic Agents administration & dosage, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents pharmacology, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Antineoplastic Combined Chemotherapy Protocols metabolism, Antineoplastic Combined Chemotherapy Protocols pharmacokinetics, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Cell Line, Tumor, Cell Survival drug effects, DNA, Antisense administration & dosage, DNA, Antisense pharmacokinetics, DNA, Antisense pharmacology, DNA, Single-Stranded administration & dosage, DNA, Single-Stranded pharmacokinetics, DNA, Single-Stranded pharmacology, Drug Compounding, Drug Stability, Female, Liposomes, Mice, Mice, Inbred BALB C, Mice, Nude, Mice, SCID, Neoplasms blood, Oligodeoxyribonucleotides chemistry, Oligodeoxyribonucleotides pharmacokinetics, Oligodeoxyribonucleotides pharmacology, Oligodeoxyribonucleotides therapeutic use, Pharmaceutical Vehicles, Proto-Oncogene Proteins c-bcl-2 genetics, Proto-Oncogene Proteins c-bcl-2 metabolism, Random Allocation, Xenograft Model Antitumor Assays, Antineoplastic Agents therapeutic use, DNA, Antisense therapeutic use, DNA, Single-Stranded therapeutic use, Gene Silencing drug effects, Neoplasms drug therapy, Proto-Oncogene Proteins c-bcl-2 antagonists & inhibitors
- Abstract
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.
- Published
- 2014
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