Preservation of immune effector cell function following administration of a dose-intense 5-fluorouracil-chemotherapy regimen

Abstract

In a phase II clinical trial of 5-fluorouracil (5FU) plus N-(phosphonacetyl)-L-aspartate (PALA) therapy administration, a number of slowly developing clinical responses were observed. Because of this, a variety of immune parameters were sequentially studied in 21 patients on this trial. Of the 21 patients studied, 20 provided sufficient samples to compare baseline with subsequent values, 10 of the 20 patients responded to treatment. Responders and non-responders did not differ in any studied parameter at baseline. After 2 months of therapy, non-specific monocyte cytotoxicity (NSMC), antibody-dependent monocyte cytotoxicity (ADMC) and natural killer (NK) activity were higher in the entire study population, but these increases were not statistically significant. When responders and non-responders were evaluated separately, it was apparent that the trend was due solely to the changes observed in the responding patient population. When mean lysis values for each patient group were determined for each studied time point, it was possible to generate a mean area under the cytotoxicity/time curve (AUC) for each studied parameter. NSMC and ADMC did not differ in responders and non-responders. However, NK activity was significantly greater by mean AUC analysis (P = 0.006) in the responding group; NK activity was maintained in the responders, but decreased in non-responders. When lymphocyte and monocyte expression of the surface markers beta 2-microglobulin, HLA-DR, CD56, HNK-1, CD16 and interleukin-2 receptor were evaluated, there were no differences among responders and non-responders at baseline by mean AUC analysis or when comparing baseline with non-baseline values. It is concluded that although baseline immunological characteristics do not identify patients who are likely to respond to weekly 5FU and PALA, treatment is not associated with deleterious effects on the immune effector function parameters evaluated in this study, there being no effects on expression of a variety of associated cell-surface molecules.

The effect of colorectal cancer upon host peripheral immune cell function

“…These results provide further evidence of a shift in immunity in patients with colorectal cancer, specifically with suppression of CMI, which has ramifications in terms of the development of malignant disease both locally and systemically. This suggests that a significant proportion of colorectal cancers may be amenable to modulation with CMI ⁄ TH1 enhancing agents, especially if combined with other modalities including anti-inflammatory and anti-angiogenic therapies as well as standard chemotherapy regimes which have already been demonstrated to preserve immune effector cell function [39]. Given the multitude of mechanisms through which tumours have managed to escape and suppress host immunity it may be necessary to combine immunotherapeutic agents to produce a multi-targeted immune response as is seen when using an autologous haemoderivative [40].…”

Retinol May Promote Fluorouracil-Suppressed Healing of Experimental Intestinal Anastomoses

“…It has been suggested that fluorouracil-based chemotherapy is associated with suppression of immune function. 27 Thus, perioperative fluorouracil therapy might result in depressed function of macrophages and lym¬ phocytes. Stimulation of these cells might improve fluorouracil-suppressed healing.…”

Review article: immune suppression and colorectal cancer

“…We therefore propose that the case for further studies with cancer vaccine and other immunotherapy candidates is overwhelming for Dukes’ B disease and should be incorporated with standard adjuvant therapies for more advanced disease. Of note is the fact that current adjuvant regimens are remarkably non‐immunosuppressive and would therefore be ideal for combination studies 214 …”