Improved Antitumor Activity of the Fluoropyrimidine Polymer CF10 in Preclinical Colorectal Cancer Models through Distinct Mechanistic and Pharmacologic Properties.

Chemotherapy regimens that include 5-fluorouracil (5-FU) are central to colorectal cancer treatment; however, risk/benefit concerns limit 5-FU's use, necessitating development of improved fluoropyrimidine (FP) drugs. In our study, we evaluated a second-generation nanoscale FP polymer, CF10, for improved antitumor activity. CF10 was more potent than the prototype FP polymer F10 and much more potent than 5-FU in multiple colorectal cancer cell lines including HCT-116, LS174T, SW480, and T84D. CF10 displayed improved stability to exonuclease degradation relative to F10 and reduced susceptibility to thymidine antagonism due to extension of the polymer with arabinosyl cytidine. In colorectal cancer cells, CF10 strongly inhibited thymidylate synthase (TS), induced Top1 cleavage complex formation and caused replication stress, while similar concentrations of 5-FU were ineffective. CF10 was well tolerated in vivo and invoked a reduced inflammatory response relative to 5-FU. Blood chemistry parameters in CF10-treated mice were within normal limits. In vivo, CF10 displayed antitumor activity in several colorectal cancer flank tumor models including HCT-116, HT-29, and CT-26. CF10's antitumor activity was associated with increased plasma levels of FP deoxynucleotide metabolites relative to 5-FU. CF10 significantly reduced tumor growth and improved survival (84.5 days vs. 32 days; P < 0.0001) relative to 5-FU in an orthotopic HCT-116-luc colorectal cancer model that spontaneously metastasized to liver. Improved survival in the orthotopic model correlated with localization of a fluorescent CF10 conjugate to tumor. Together, our preclinical data support an early-phase clinical trial of CF10 for treatment of colorectal cancer.

Prostate-specific membrane antigen-targeted liposomes specifically deliver the Zn(2+) chelator TPEN inducing oxidative stress in prostate cancer cells.

AIM: To evaluate the potential use of zinc chelation for prostate cancer therapy using a new liposomal formulation of the zinc chelator, N,N,N',N'-tetrakis(2-pyridylmethyl)-ethylenediamine (TPEN). MATERIALS & METHODS: TPEN was encapsulated in nontargeted liposomes or liposomes displaying an aptamer to target prostate cancer cells overexpression prostate-specific membrane antigen. The prostate cancer selectivity and therapeutic efficacy of liposomal (targeted and nontargeted) and free TPEN were evaluated in vitro and in tumor-bearing mice. RESULTS & CONCLUSION: TPEN chelates zinc and results in reactive oxygen species imbalance leading to cell death. Delivery of TPEN using aptamer-targeted liposomes results in specific delivery to targeted cells. In vivo experiments show that TPEN-loaded, aptamer-targeted liposomes reduce tumor growth in a human prostate cancer xenograft model.

Clinical and microbial evaluation of a histatin-containing mouthrinse in humans with experimental gingivitis: a phase-2 multi-center study.

OBJECTIVE: P-113, a 12 amino acid histatin-based peptide, was evaluated in a mouthrinse formulation for safety and efficacy in a phase 2 multi-center clinical study. METHOD: 294 healthy subjects abstained from oral hygiene procedures and self-administered either 0.01% P-113, 0.03% P-113 or placebo mouthrinse formulations twice daily over a 4-week treatment period. During this time, the safety, anti-gingivitis, and anti-plaque effects of P-113 were evaluated. RESULTS: There was a significant reduction in the change from baseline to Day 22 in bleeding on probing in the 0.01% P-113 treatment group of the intent to treat population (p=0.049). Non-significant trends in the reduction of the other parameters were observed in this population (p> or =0.159). A sub-group of subjects which developed significant levels of disease within the four-week timeframe of the study was identified based on baseline gingival index scores > or =0.75. Significant findings were observed for bleeding on probing, gingival index and plaque index within this population (p<0.05). There were no treatment-related adverse events, and there were no adverse shifts in supragingival microflora during the study. Significant amounts of the peptide were retained in the oral cavity following rinsing. CONCLUSION: These data suggest that P-113 mouthrinse is safe and reduces the development of gingival bleeding, gingivitis and plaque in the human experimental gingivitis model.