Antitumor activity of tumor necrosis factor-alpha conjugated with polyvinylpyrrolidone on solid tumors in mice

Cancer Res. 2000 Nov 15;60(22):6416-20.

Abstract

We attempted the development of a novel polymer conjugation to further improve the therapeutic potency of antitumor cytokines compared with PEGylation for clinical application. Compared with native tumor necrosis factor (TNF)-alpha in vitro, specific bioactivities of polyvinyl-pyrrolidone (PVP)-modified TNF-alphas (PVP-TNF-alphas) were decreased by increasing the degree of PVP attachment. PVP-TNF-alpha fraction 3, Mr 101,000, had the most effective antitumor activity of the various PVP-TNF-alphas in vivo. PVP-TNF-alpha fraction 3 had >200-fold higher antitumor effect than native TNF-alpha, and the antitumor activity of PVP-TNF-alpha fraction 3 was >2-fold higher than that of MPEG-TNF-alpha (Mr 108,000), which had the highest antitumor activity among the polyethylene glycol (PEG)-conjugated TNF-alphas. Additionally, a high dose of native TNF-alpha induced toxic side effects such as body weight reduction, piloerection. and tissue inflammation, whereas no side effects were observed after i.v. administration of PVP-TNF-alpha fraction 3. The plasma half-life of PVP-TNF-alpha fraction 3 (360 min) was about 80- and 3-fold longer than those of native TNF-alpha (4.6 mm) and MPEG-TNF-alpha (122 min), respectively. The mechanism of increased antitumor effect in vivo caused the prolongation of plasma half-life and increase in stability. These results suggested that PVP is a useful polymeric modifier for bioconjugation of TNF-alpha to increase its antitumor potency, and multifunctionally bioconjugated TNF-alpha may be a potentiated antitumor agent for clinical use.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacokinetics
  • Drug Carriers
  • Female
  • Fibrosarcoma / drug therapy
  • Fibrosarcoma / metabolism
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Neoplasm Transplantation
  • Pharmaceutic Aids / administration & dosage*
  • Pharmaceutic Aids / chemistry
  • Pharmaceutic Aids / pharmacokinetics
  • Polyethylene Glycols / administration & dosage
  • Polyethylene Glycols / chemistry
  • Polyethylene Glycols / pharmacokinetics
  • Povidone / administration & dosage*
  • Povidone / chemistry
  • Povidone / pharmacokinetics
  • Sarcoma 180 / drug therapy
  • Sarcoma 180 / metabolism
  • Tumor Necrosis Factor-alpha / administration & dosage*
  • Tumor Necrosis Factor-alpha / chemistry
  • Tumor Necrosis Factor-alpha / pharmacokinetics

Substances

  • Antineoplastic Agents
  • Drug Carriers
  • Pharmaceutic Aids
  • Tumor Necrosis Factor-alpha
  • Polyethylene Glycols
  • Povidone