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Intra-arterial administration of TNF-α followed by arterial ablation is an effective therapy for a regionally confined TNF-resistant rat mammary adenocarcinoma

  • Author(s): Badgwell, BD
  • Valentino, DJ
  • Jeffes, EWB
  • Dieffenbach, K
  • Dulkanchainun, SB
  • Yamamoto, RS
  • Granger, GA
  • Jakowatz, JG
  • Carson, WE
  • et al.
Creative Commons Attribution 4.0 International Public License
Abstract

Tumor necrosis factor-alpha (TNF-α) is an immunomodulatory cytokine that has exhibited anti-tumor activity in a variety of experimental systems. However, the toxicities associated with systemic administration of TNF-α have limited its clinical utility and have led to the investigation of targeted delivery techniques with the ability to present the TNF-α dose directly to the vascular bed of the tumor. The intra-arterial (IA) administration of TNF-α to patients with liver metastases represents one such approach, and recent work suggests that subsequent ablation of the tumor's arterial supply via embolization may enhance the efficacy of intra-arterial treatments (hepatic chemoembolization). The present study was undertaken to test the hypothesis that IA administration of TNF-α is superior to the intravenous (IV) route for inhibition of tumor growth in a regionally confined rat mammary adenocarcinoma model that provides for ablation of the arterial supply to the tumor following cytokine therapy. Rats bearing hind limb mammary adenocarcinomas received single IA or IV infusions of 8×105, 1×106, and 1.5×106units of TNF-α via the common femoral artery (CFA) followed 1 h later by ligation of the artery. Control animals received either no treatment or IA infusion of 2% normal rat serum (NRS) followed by ipsilateral CFA ligation. Tumor size was measured every other day after treatment. Tumor growth inhibition occurred in the first 5 to 10 days after treatment. IV administration of TNF-α did not result in visual tumor necrosis or significant reduction in the rate of tumor growth. IA administration of TNF-α resulted in statistically significant diminution of tumor size as compared to untreated controls and animals receiving IA 2% normal rat serum (NRS; P < 0.05 at days 6, 8 and 10), regardless of the dose employed. The maximum growth inhibition with IA TNF-α was a 91% reduction in tumor volume that was achieved with a dose of 1×106U TNF-α. These results demonstrate improved anti-tumor activity with the IA administration of TNF-α over the IV route in a regionally confined mammary adenocarcinoma. IA administration of biologic response modifiers like TNF-α may therefore be a useful approach for the hepatic chemoembolization of breast adenocarcinomas metastatic to the liver.

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