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Timing of surgery in premenopausal patients with breast cancer remains controversial. Angiogenesis is essential for tumour growth and vascular endothelial growth factor (VEGF) is one of the most potent angiogenic cytokines. We aimed to determine whether the study of VEGF in relation to the menstrual cycle could help further the understanding of this issue of surgical intervention. Fourteen premenopausal women were recruited, along with three post-menopausal women, a woman on an oral contraceptive pill and a single male subject. Between eight and 11 samples were taken per person, over one menstrual cycle (over 1 month in the five controls) and analysed for sex hormones and VEGF165. Serum VEGF was significantly lower in the luteal phase and showed a significant negative correlation with progesterone in all 14 premenopausal women. No inter-sample variations of VEGF were noted in the controls. Serum from both phases of the cycle from one subject was added to MCF-7 breast cancer cells; VEGF expression in the supernatant was lower in the cells to which the luteal phase serum was added. The lowering of a potent angiogenic cytokine in the luteal phase suggests a possible decreased potential for micrometastasis establishment in that phase. This fall in VEGF may be an effect of progesterone and should be the focus of future studies.

Antibodies are thought to bring about tumour cell lysis by antibody-dependent cell-mediated cytotoxicity (ADCC), but the exact mechanism is not well elucidated. Monocytes are known to be important mediators of anti-tumour ADCC and are also known to secrete the cytokines tumour necrosis factor alpha (TNF-alpha) and interleukin 1 beta (IL-1 beta), both of which have been shown to bring about tumour cell lysis. We examined the release of these cytokines during ADCC and attempted to elucidate which components of the ADCC reaction were necessary for cytokine production. We measured TNF-alpha and IL-1 beta in supernatants collected from a standard ADCC assay using each of the anti-colorectal antibodies m17-1A, c17-1A and cSF25. We found that there was significant TNF-alpha and IL-1 beta release during ADCC mediated by each of these three antibodies and that the magnitude of cytokine release seemed to reflect the degree of tumour cell lysis produced by each antibody. Furthermore, we found that effector cells, target cells and a specific anti-tumour antibody were necessary for this to occur. The presence of only some of the components of the reaction or of an irrelevant antibody produced little or no TNF-alpha or IL-1 beta. We conclude that TNF-alpha and IL-1 beta are released when an effector and tumour target cell are united by a specific tumour antibody and that these cytokines may be important in bringing about tumour cell lysis during the ADCC reaction.

The anti-tumour antibody-dependent cell-mediated cytotoxicity (ADCC) capacity of the conventional antibody m17-1A was compared with its chimerised analogue c17-1A and a newer chimeric antibody, cSF25, specific for colonic adenocarcinoma. The results (AUC units +/- s.e.m., control versus cancer) show that mononuclear cells from patients with adenocarcinoma mediate ADCC as efficiently as those from controls for m17-1A (143 +/- 14 vs 153 +/- 14), c17-1A (174 +/- 16 vs 189 +/- 14) cSF25 (215 +/- 18 vs 237 +/- 13) and effectors and targets alone (57 +/- 9 vs 51 +/- 8). Both chimeric antibodies mediated ADCC more effectively than m17-1A with cSF25 consistently producing the highest lysis. Furthermore, more efficient ADCC was found to correspond with monocyte activation examined flow cytometrically. The results (mean channel fluorescence) show that HLA-DR expression is increased with c17-1A (1436 +/- 200) and cSF25 (2252 +/- 298) above that observed when effectors and targets were incubated alone (1157 +/- 168) or with m17-1A (1286 +/- 170). Similarly, interleukin 2 receptor (IL-2R) expression (percentage of positive cells) was augmented in the presence of m17-1A (15 +/- 3), c17-1A (14 +/- 3) and cSF25 (25 +/- 3) when compared with no antibody (9 +/- 2). We discuss the possibility that the superior ADCC activity of chimeric antibodies, especially cSF25, may be due to increased monocyte activation.

Thyroid dysfunction is a well-recognised side-effect of treatment with interleukin-2 (IL2). We assessed the correlation between the development of abnormal thyroid function and tumour response in 13 patients receiving IL2 and interferon-2 alpha (IFN2 alpha) for advanced malignancy. Seven patients had normal thyroid function during treatment, and all of these patients have since died of progressive disease. Of six patients who did develop thyroid dysfunction during treatment, one patient has died of progressive disease. However, statistically we were unable to confirm a definite correlation between the development of thyroid dysfunction and survival in this small group of patients.