Cooperative Antitumor Effect of Mixed Backbone Oligonucleotides Targeting Protein Kinase A in Combination with Cytotoxic Drugs or Biologic Agents

Caputo, Roberta; Damiano,; Bianco, Roberto; Pepe, Stefano; Pomatico, G; Bianco, A. R.; Jiang, Zhiwei; Agrawal, Sudhir; Ciardiello, F.

doi:10.1089/oli.1.1998.8.141

Cited by 11 publications

(1 citation statement)

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“…PO and PS are 20-mer antisense to human oncogene c-myc. PS-OMe is a second-generation 18-mer antisense oligonucleotide targeted to PKA, a signal-transducing protein playing a key role in the control of cell growth and differentiation, which is present in mammalian cells (ChoChung, 1997;Tortora et al, 1998Tortora et al, , 1999Ciardielloet al, 1998). The second-generation oligonucleotide showed reduced toxicity and significant antitumor effects in a tumor-bearing nude mouse model (Agrawal and Zhao, 1998a).…”

Section: Discussionmentioning

confidence: 99%

Intratumoral Pharmacokinetics of Oligonucleotides in a Tissue-Isolated Tumor Perfusion System

Nakajima¹,

Koshino²,

Nomura³

et al. 2000

Antisense and Nucleic Acid Drug Development

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The intratumoral pharmacokinetics of model oligonucleotides were studied in Walker 256 tissue-isolated tumor preparations using an in situ single-pass vascular perfusion technique. A 20-mer phosphodiester (PO) oligonucleotide, its fully phosphorothioated (PS) oligonucleotide counterpart, and an 18-mer phosphorothioated oligonucleotide containing four 2'-O-methylribonucleosides at both the 3'-end and 5'-end (PS-OMe) were used. These oligonucleotides were administered to the tumor in two ways, by constant arterial infusion and by direct intratumoral injection. In the case of constant arterial infusion, the experiments were carried out using perfusate with or without 4.7% bovine serum albumin (BSA). The protein binding of PO, PS, and PS-OMe to BSA was 46%, 87%, and 94%, respectively. No marked difference was observed between the degree of accumulation of the three types of oligonucleotides in the tumor when BSA was present in the perfusate. PS and PS-OMe showed higher degrees of accumulation in tumors compared with PO when no BSA was present. These results indicate that free (i.e., protein unbound) PS-OMe and PS have superior tumor accumulation characteristics. In the intratumoral injection experiments, PS-OMe was retained longer in tumor tissue compared with PS, suggesting that it might be useful for direct local injection into solid tumors. Thus, the present study provides useful information about the basic disposition characteristics of oligonucleotides in solid tumors.

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Section: Discussionmentioning

confidence: 99%