Effects of recombinant tumour necrosis factor (rTNF‐α) in cancer. Observations on the acute phase protein reaction and immunoglobulin synthesis after high dose recombinant TNF‐α administration in isolated limb perfusions in cancer patients

Abstract

To obtain insight in the effect of TNF on the synthesis of acute phase proteins like CRP, alpha 1-antitrypsine, alpha 1-acidglycoprotein, C3 and C4 and the immunoglobulins (IgG-M-A), nine cancer patients who were treated with an isolated limb perfusion (ILP) with high dose recombinant TNF-alpha (rTNF-alpha) were investigated during a 7-day period after the end of the perfusion. Resorption of rTNF-alpha from out of these limbs into the circulation after the ILP induced within 30 min to 6 h in all patients elevated serum levels of IL-6. At the same time C-reactive protein became detectable in serum. The highest serum levels were obtained at 48 h after ILP. The serum levels of the other acute phase proteins (alpha 1-acidglycoprotein, alpha 1-antirypsine, C3, C4), rose more slowly and the highest serum levels were found at the third day. All investigated proteins declined after they had reached their peak levels. Levels of alpha 1-acidglycoprotein and alpha 1-anti-trypsin alpha 1-acid declined slower than both complement component. In regard to the immunoglobulin levels a nearly continuous increase in the serum level of specifically IgM was observed. This study clearly shows the interrelationship between TNF-alpha and IL-6 in regard to the synthesis of the different acute phase proteins; and moreover also a striking effect on IgM synthesis.

Absence of Severe Systemic Toxicity After Leakage-Controlled Isolated Limb Perfusion With Tumor Necrosis Factor-α and Melphalan

“…The 20 patients each participated in one of the three pharmacokinetic studies conducted at our institutions. [17][18][19][20] For eight patients, 18 blood from the perfusion circuit and systemic circulation was obtained immediately before the start of treatment with cytokines (at Ϫ1 minute; baseline), at 5 minutes after TNF-␣ administration, and at the end of ILP but before reconnection of the limb circulation (at 89 minutes). After restoration of the physiological limb circulation, systemic blood samples were collected at 1, 5, 10, 30, 60, 120, 180, 240, 360, 420, and 480 minutes, as well as the next morning.…”

Outcome and prognostic factor analysis of 217 consecutive isolated limb perfusions with tumor necrosis factor‐α and melphalan for limb‐threatening soft tissue sarcoma

“…Systemic toxicity is directly correlated with leakage of TNF (and melphalan) to the systemic circulation. [41][42][43] In the present time of leakage-free ILPs, it should not be necessary to use vasopressors in order to keep the blood pressure at adequate levels to counteract the systemic inflammatory response syndrome that can occur when significant levels of TNF reach the systemic circulation. Ample hydration and adequate diuresis in order to keep the levels of circulating TNF after ILP low should prevent systemic toxicity even in high-leakage ILPs.…”

Clinical Management and Current Research in Isolated Limb Perfusion for Sarcoma and Melanoma

“…IL-6 is the major regulator of the acutephase proteins [94] being elevated after ILP with rhTNF-·. In a series of 9 patients, Swaak et al [95] found a peak Hohenberger/Kettelhack concentration of C-reactive protein after 48 h. The levels of other acute-phase proteins (· 1 -antitrypsin, · 1 -acid glycoprotein, complement factors C3 and C4) rose until the third day. In parallel, an increase in IgM synthesis was reported demonstrating that TNF-· stimulates immunoglobulin synthesis in vivo.…”

“…In experimental tumors in vivo, TNF-· induces hemorrhagic necrosis [61] 95 action [73]. The activity of rhTNF-· in ILP is based on the multiple actions of TNF on endothelial cells in the tumor vascular system and only tumors with microvascularization can be destroyed by TNF [74].…”