title: Keeping those telomeres short! an innovative intratumoral long-term drug delivery system.
abstract: BACKGROUND
  Telomerase activation and an alternative lengthening of telomeres (ALT) mechanism are two telomere-lengthening cancer cell survival mechanisms elicited by both chemo- and/or radiotherapy. Telomere lengthening interferes with cell lethality and results in the immortalization of cancer cells. To counteract these mechanisms, we developed a drug delivery system (DDS) consisting of a polymeric implant that is inserted directly into tumors. The DDS releases, continuously and gradually, a cationic porphyrin (PdTMPyP4) for >30 days after a single application, and inhibits telomerase activation.
  
  
  METHODS
  The PdTMPyP4 porphyrin is incorporated into a poly(co-glycolic lactic)acid (PLGA) polymer, solidified and cut into small rods. PdTMPyP4 release from the rods was measured spectrophotometrically over time. Uptake of Pd in the DNA of in L428 Hodgkins lymphoma cells was measured by ICP-MS, and telomerase activation by the TRAP assay. The rods were placed into the growth medium of cells whose growth rate was measured for 11 and 19 days. The cylinders were also inserted directly into KHJJ murine mammary tumors borne on the thighs of BALB/c mice and the tumor growth rate measured.
  
  
  RESULTS
  In vitro, >10(9)Pd atoms were measured in the DNA of each L428 cell and telomerase activity was reduced by ~15% within 24 h. A one-time application of the rod in the cell medium induced a factor of >5 greater lethality compared to a blank rod or untreated controls. In vivo, a one-time insertion of the rod into tumors resulted in the retardation of the growth rate by factors of 3-5 compared to untreated controls. Systemic uptake after intratumoral insertion of the rod was negligible.
  
  
  CONCLUSIONS
  The results suggest that the direct intratumoral insertion of a PdTMPyP4-containing polymeric rod would be of benefit as an adjuvant treatment for patients undergoing chemo- or radiotherapy. By preventing the lengthening of telomeres and therefore the unrestricted growth of cancer cells, our DDS will provide a significant therapeutic advantage to these treatments without affecting normal tissues.
authors: Jerry J. Cohen Radiobiology Research Laboratory, Ben Gurion University, 84105, Beer Sheva, Israel, blaster@bgu.ac.il.
authors: B H
authors: BH
authors: Laster
authors: C
authors: C
authors: Isaacson
authors: E
authors: E
authors: Perets
authors: M
authors: M
authors: Msamra
authors: E
authors: E
authors: Priel
authors: J
authors: J
authors: Kalef-Ezra
authors: J
authors: J
authors: Kost
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D004273:DNA, Neoplasm / Q000235:genetics; D016503:Drug Delivery Systems; D005260:Female; D006689:Hodgkin Disease / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D010165:Palladium / Q000737:chemistry; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011166:Porphyrins / Q000008:administration & dosage* / Q000494:pharmacology; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000235:genetics*; D014407:Tumor Cells, Cultured
chemical_list: D020533:Angiogenesis Inhibitors; D004273:DNA, Neoplasm; D011166:Porphyrins; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; C021096:tetra(4-N-methylpyridyl)porphine; D010165:Palladium; D019098:Telomerase