Acute effects of pamidronate administration on serum levels of interleukin-6 in advanced solid tumour patients with bone metastases and their possible implications in the immunotherapy of cancer with interleukin-2.

Bisphosphonates are potent inhibitors of bone resorption and are commonly used in the treatment of bone metastases. In addition, they seem to influence cytokine secretion. Since the efficacy of IL-2 cancer immunotherapy, in part, depends on endogenous cytokine secretion, bisphosphonates could be effective in modulating IL-2 activity. High pretreatment levels of IL-6 seem to correlate with resistance to IL-2. On this basis, a pilot study was performed to evaluate the in vivo effects of the bisphosphonate, pamidronate, on blood levels of IL-6. The study included 7 patients with bone metastases due to solid tumours. Pamidronate was injected intravenously at 60 mg over 3 h. Venous blood samples were drawn before, at 1-h intervals during pamidronate infusion, then after 1 and 3 days. Mean serum levels of IL-6 significantly decreased during pamidronate infusion, then after 1 and 3 days, IL-6 mean levels still remained lower than control level, but differences were not significant. This preliminary study shows that pamidronate infusion induces a rapid but transient decline in IL-6 blood concentrations, and suggests a possible use of bisphosphonates to modulate the efficacy of IL-2 cancer immunotherapy.

Interleukin-12 in early or advanced cancer patients.

Interleukin-2 (IL-2) and interleukin-12 (IL-12) may represent the most important antitumour cytokines in human neoplasms. IL-2 blood levels decrease in advanced solid malignancies, but currently there are no data on IL-12 secretion in cancer patients. This study was performed to obtain preliminary data about IL-12 secretion in patients with solid malignant tumours, either in relation to the extension of disease, or to other cytokines, including IL-2, IL-6 and IL-10. The study included 40 solid cancer patients, 24 of whom showed distant organ metastases. Cytokine serum levels were measured by an enzyme immunoassay of blood samples collected during the morning. No patient had abnormally low levels of IL-12, but the levels were high in 14/14 (35%) patients. Mean levels of IL-12 were significantly higher in metastatic patients compared with non-metastatic patients (P < 0.05). Moreover, metastatic patients with high blood concentrations of IL-12 showed significantly lower levels of IL-10 than metastatic patients with normal IL-12 values, while no difference was seen in IL-2 mean concentrations. IL-6 mean levels were lower in metastatic patients with increased IL-12 levels, but this was non-significant. This preliminary study shows that advanced solid cancers are not characterised by a diminished secretion of IL-12, but rather IL-12 levels tend to be abnormally high in metastatic cancer patients.

Enhancement of the efficacy of weekly low-dose taxotere by the long acting anti-prolactinemic drug cabergoline in pretreated metastatic breast cancer.

In view of its potential action as a growth factor, the evidence of abnormally high blood levels of prolactin (PRL) is associated with a poor prognosis in metastatic breast cancer. Moreover, metastatic breast cancer-related hyperprolactinemia has proven to counteract the efficacy of cancer chemotherapy. The negative influence of high blood levels of PRL on the efficacy of chemotherapy in metastatic breast cancer has been confirmed by previous preliminary studies, showing that the concomitant administration of the anti-prolactinemic dopaminergic agent bromocriptine may enhance the therapeutic effect of chemotherapy. However, the clinical use of bromocriptine is limited by its short duration and gastrointestinal toxicity. Therefore, new anti-prolactinemic drugs, characterized by less toxicity and a longer duration of activity, such as Cabergoline (CBG), could be more appropriated to control PRL secretion in breast cancer. On this basis, a study was planned to evaluate the efficacy and tolerability of a concomitant administration of CBG with weekly low-dose Taxotere (TXT) in pretreated metastatic breast cancer under chemotherapy. The study group comprised 70 metastatic breast cancer patients (females), pretreated with at least one previous chemotherapeutic line containing anthracyclines, who were randomized to be treated with TXT alone or TXT plus CBG. TXT 25 mg/m2 was given i.v. at weekly intervals for at least 9 consecutive cycles. CBG was given orally at 0.5 mg once per week. Abnormally high pre-treatment levels of PRL were seen in 24/70 (34%) patients, 11 of whom were treated with TXT plus CBG, whereas the other 13 received TXT alone. CBG induced a complete normalization of the PRL levels in all patients within the first two weeks of therapy, whereas no normalization of PRL occurred spontaneously in patients treated with chemotherapy alone. The objective tumor regression rate was significantly higher in patients concomitantly treated with CBG than in those who received chemotherapy alone (31/34 vs 13/36, p < 0.05), and this difference was particularly evident in patients with high PRL levels prior to therapy (6/11 vs 2/13). No CBG-related toxicity occurred. On the contrary, chemotherapy-induced asthenia was significantly lower in patients concomitantly treated with CBG (5/34 vs 11/36, p < 0.05). This study shows that the chemoneuroendocrine therapy of weekly low-dose TXT plus the anti-prolactinemic drug CBG is a new, effective and well-tolerated therapy for metastatic breast cancer. It may also be recommended in heavily pretreated patients or in those with poor clinical status.

Abrogation of surgery-induced IL-6 hypersecretion by presurgical immunotherapy with IL-2 and its importance in the prevention of postoperative complications.

Because of its immunosuppressive effect, surgery-induced immunosuppression may depend at least in part on the postoperative hypersecretion of IL-6, which is also responsible for surgical complications. Most of the immunosuppressive events induced by surgery, including lymphocytopenia, NK and T lymphocyte decline, and dendritic cell deficiency have been proven to be abrogated by a preoperative injection of IL-2 for few days. However, the cytokine mechanisms responsible for IL-2-induced abrogation of surgery-related immunosuppression need to be better investigated and understood. This study was performed to analyze the influence of IL-2 presurgical immunotherapy on IL-6 secretion in the postoperative period. The study was performed in 12 operable colorectal cancer patients, who were preoperatively pretreated with IL-2 (12 million lU/day subcutaneously for 3 consecutive days before surgery). The control group consisted of 21 age-and disease-matched colorectal cancer patients who underwent surgery without a preoperative immunotherapy with IL-2. Serum levels of IL-6 were measured by an enzyme immunoassay before surgery, and at days 3 and 7 of the postoperative period. A significant increase in mean serum levels of IL-6 occurred in the postoperative period only in the control patients, whereas in the IL-2 pretreated group no significant difference was seen between presurgical and postoperative IL-6 mean concentrations. The difference between controls and IL-2 group was particularly evident for patients with abnormally elevated presurgical values of IL-6. This study, by showing that a presurgical injection of IL-2 may prevent surgery-induced IL-6 enhanced secretion, would suggest that the previously described neutralization of surgery-induced immunosuppression by IL-2 preoperative immunotherapy may depend at least in part on the inhibition of postoperative production of IL-6, whose immunosuppressive effects have been well demonstrated at least on anticancer immunity.

Inhibition of tumor necrosis factor-alpha secretion by pentoxifylline in advanced cancer patients with abnormally high blood levels of tumor necrosis factor-alpha.

TNF, in addition to its antitumor activity, would play an important role in the pathogenesis of cancer-related severe complications, including ARDS and DIC. Therefore, the modulation of TNF secretion could be important in the supportive care of advanced cancer patients. At present, PTX is the only drug which has been proven to be able to inhibit in vitro the release of TNF. The present study was performed to evaluate the effect of PTX on TNF blood concentrations in disseminated cancer patients with abnormally high TNF values. The study included 14 cancer patients, with initial or conclamate signs of ARDS (n = 8) or DIC (n = 6). PTX was given intravenously at a dose of 300 mg/day for 7 days. Mean serum levels of TNF significantly decreased in response to PTX therapy, and they returned to normal range in 5/14 patients. These preliminary data would suggest that PTX may be considered as a biological response modifier, capable of inhibiting TNF secretion in humans, with a following potential use in the treatment of cancer-related severe complications.

Effects of granulocyte-macrophage colony stimulating factor on soluble interleukin-2 receptor serum levels and their relation to neopterin and tumor necrosis factor-alpha in cancer patients.

SIL-2R levels mainly depend on a T lymphocyte production. The mechanisms responsible for the elevated blood concentrations of SIL-2R in advanced solid tumors are still unknown. To investigate the role played by the monocyte-macrophage system on SIL-2R release, we have evaluated serum levels of SIL-2R in 10 head and neck cancer patients during GM-CSF subcutaneous administration (3 mcg/kg/day for 11 consecutive days). Serum levels of TNF and neopterin, both produced by macrophages, were also measured. SIL-2R mean concentration significantly enhanced in response to GM-CSF, and their rise positively correlated to that in TNF and neopterin values, while lymphocyte mean number did not increase during the study. The present results represent the first in vivo demonstration that SIL-2R release is related to macrophage activation, rather than to depend only on lymphocyte proliferation.

Tumor necrosis factor in solid tumors: increased blood levels in the metastatic disease.

TNF, a cytokine produced by macrophages, is able either to exert an antitumor activity, or to determine severe clinical complications, such as cachexia and septic shock. Increased blood levels of TNF have been described in cancer patients. The present study was performed to better define TNF secretion in patients with solid tumors. The study included 48 cancer patients (lung cancer: 22; colon cancer: 11; breast cancer: 10; renal cancer: 5), and among them 27 showed distant organ metastases. TNF serum levels were measured by IRMA method. The control group comprised 40 healthy subjects. TNF levels were also evaluated in relation to those of SIL-2R, whose increase seems to be associated with an unfavorable prognosis in cancer. High levels of TNF were seen in 27/48 (56%) patients. Mean levels of TNF were significantly higher in cancer patients than in controls. Moreover, within the cancer group, TNF mean values were significantly higher in metastatic patients than in those without metastases; the highest levels were observed in patients with visceral lesions as dominant metastasis sites. Finally, patients with high TNF concentrations showed significantly higher mean levels of SIL-2R than those with normal values. This study shows that the neoplastic metastatic disease is associated with an exaggerated TNF secretion.

Clinical significance of erythrosedimentation rate in cancer in relation to cytokine production: correlation with high IL-6 and low IL-2 blood concentrations.

Despite its well documented unfavourable prognostic significance in several human diseases, including cancer, the cytokinic mechanisms responsible for an increased erythrosedimentation rate (ESR) still remain to be better analyzed and defined. The recent possibility to measure cytokine concentrations in the blood of patients has allowed us to explore the possible relation between ESR values and endogenous cytokine secretions. This preliminary study was performed to evaluate the relationship between ESR values and serum levels of IL-2 and IL-6, which represent the most important cytokines responsible for the activation and the suppression, respectively, of host anticancer immune reaction. The study included 33 consecutive solid tumor patients, 22 of whom showed distant organ metastases. Abnormally high values of ESR were present in 21 patients, including 18/22 metastatic patients and 3/11 nonmetastatic patients. Patients with elevated values of ESR showed significantly higher mean levels of IL-6 and significantly lower mean concentrations of IL-2 with respect to those found in patients with normal ESR values. These results would show that cancer-related increase in ESR values is associated with low levels of IL-2 and high levels of IL-6. Since IL-2 plays an essential role in the anticancer immunity and IL-6 may suppress the antitumor immune defenses, the evidence of low levels of IL-2 and high values of IL-6 in cancer patients with increased ESR values would explain the unfavourable prognostic significance of high ESR values in human neoplasms.

Decrease in cholesterol levels during the immunotherapy of cancer with interleukin-2.

IL-2, in addition to its immunomodulating and antitumour properties, induces important systemic actions, including cardiovascular, neuroendocrine and metabolic effects. The present study was carried out to evaluate IL-2 effects on cholesterol metabolism. The study included 14 advanced cancer patients (renal carcinoma: ten; colon carcinoma: four), who received IL-2 subcutaneously at a dose of 1.8 x 10(6) IU ml-2 twice daily for 5 days/week for 6 weeks. Venous blood samples were collected 7 days before, on days 0, 3, 7, 14, 21, 42 of IL-2 therapy, and on days 14 and 28 of the rest-period. IL-2 induced a rapid and evident decrease in cholesterol levels, with a normalisation of its concentrations within 7 days in 10/10 hypercholesterolemic patients. The lowest mean levels of cholesterol were reached within the first 2 weeks; after that they still slowly increased. LDL-/HDL-cholesterol ratio was significantly reduced by IL-2 therapy. Cholesterol fall was associated with a marked increase in conjugated biliary acid levels. Finally, triglyceride values increased during IL-2 therapy, but not in a significant manner. These results, by showing that IL-2 exerts an evident and very rapid cholesterol-lowering activity, would represent a further demonstration of the physiological importance of cytokines in the control of cholesterol metabolism.