Cytokines

Cytokines are soluble proteins that mediate the interactions between the cells and their extracellular environment, in both an autocrine and paracrine manner. They exert their biological effect in a wide range of tissues, but mainly on cells of the haematopoietic and immune lineage.

Although several cytokines have been identified and characterized, their biological role is not fully understood because their physiology is particularly elaborate, since a given cytokine can both promote and inhibit tumour growth. How the cytokine will act depends on its concentration, the type of the tumour, and the temporal stage of the tumour-host relationship.

Several cytokines promise to be of therapeutic importance in oncology, including:

♦ Tumour necrosis factor (TNF)

♦ Erythropoietin

♦ Colony-stimulating factor (CSF) and interferons (IFNs)

Interferons

The interferons (IFNa-, /}, and y) are a family of proteins that are produced by the immune system in response to viral infection. They have anti-viral, anti-microbial, anti-proliferative, and immuno-modulatory activity. Anti-tumour effects of IFNs:

♦ Direct cytostatic activity

♦ Interfere with cell metabolism proliferation

♦ Modulate oncogene expression

♦ Enhance tumour-associated surface antigens

♦ Enhance cytotoxicity of natural killers (NK), macrophages, and T lymphocytes

♦ Reduce tumour neovascularization

♦ Promote differentiation of malignant cells to less aggressive types.

Interferon-a (IFN-a)

IFN-a is the treatment of choice for hairy-cell leukaemia (HCL), with a 90% response rate in the peripheral blood and 40% normalization of the bone marrow. The standard dose is 2 x 106 U/m2 given three times a week, for 6-12 months, either intramuscularly or subcuta-neously. It may induce partial or, less frequently, complete remission. Patients who relapse can be successfully retreated. The combination of IFN-a with the purine analogue 2-chlorodeoxyadenosine may be more effective for HCL patients.

IFN-a also has a first-line role in the management of chronic myeloid leukaemia (CML): IFN-a (5 x 106 U/m2 daily) exerts a marked effect on the white blood count, with 50-75% haematological remission, while prolonged administration can induce complete cytogenetic eradication, suppressing the Philadelphia chromosome-positive clone. IFN-a monotherapy increases the median survival from 3 to 5 years, while its combination with other treatment modalities increases further the clinical response.

Several phase III studies have demonstrated progression-free and overall survival when IFN-a (3-10 MU/m2 subcutaneously)was added to conventional chemotherapy to multiple myeloma patients. Up to 50% of patients with nodular (follicular) non-Hodgkin's lymphoma, refractory to conventional chemotherapy, may respond to IFN-a. Cutaneous T-cell lymphoma is another malignancy where responses of >50% can be achieved with IFN-a (6 x 106 U/m2 daily).

With regard to solid tumours, responses can be seen in 10-20% of patients with renal cell carcinoma (RCC). They usually are partial and last for 6-8 months, although complete remissions have also been reported. Responses are more often in patients with a low tumour burden, good performance status, and lung metastases only. Relatively high doses of IFN-a (10-20 x 106 U/m2 three times per week) have to be given.

IFN-a monotherapy has a moderate anti-tumour activity in malignant melanoma patients, but when combined with chemotherapy (dacarbazine) response rates are as high as 20%. Responses are usually partial, but they provide a survival benefit. IFN-a, alone or combined with zidovudine, may induce tumour responses in Kaposi's sarcoma patients, while IFN-a monotherapy has been used in carcinoid tumours. IFN-a has also been given intravesically, intraperitonally, intrapleurarly, and intralesionaly for the loco-regional treatment of cancer. Clinical uses of IFN-a:

♦ Hairy-cell leukaemia (HCL)

♦ Chronic myeloid leukaemia (CML)

♦ Multiple myeloma

♦ Non-Hodgkin's lymphoma

♦ Cutaneous T-cell lymphoma

♦ Renal cell carcinoma

♦ Malignant melanoma

♦ Kaposi's sarcoma

♦ Carcinoid tumours

IFN-6 and IFN-y

Despite the fact that only IFN-a is currently in routine clinical use, IFN-^ and IFN-y have also some anti-tumour effect. Clinically, they have been used in patients with:

♦ Multiple myeloma

♦ Renal cell carcinoma

♦ Ovarian cancer

♦ Bladder cancer

There is not enough data to support any advantage over IFN-a, or with the concomitant administration of more than one IFN.

IFN-a, alone or in combination with tamoxifen, has been used also in breast cancer patients, with poor results.

However, the combination of IFN-a and TNF has been shown to be particularly effective in preclinical models. Clinically, this combination has been used in the treatment of melanoma and sarcoma using isolated limb perfusion. IFN-a has been used also in combination with IL-2, in patients with peritoneal carcinomatosis, and with 5-fluorouracil, in patients with advanced colorectal cancer. It syner-gistically enhances LAK cell activity of IL-2. Phase I/II clinical trials are currently ongoing.

Toxicity of IFNs

The major side-effects include flu-like symptoms (fever, chills, headache, malaise), which can be relieved with paracetamol or pred-nisolone. Other toxicities include:

♦ Gastrointestinal complaints

♦ Thrombocytopenia

♦ Elevation of liver function tests

Tolerance to IFN-a increases with prolonged administration and all side-effects are reversible when treatment is discontinued.

IFNs represent an anti-neoplastic agent, effective for some malignancies resistant to conventional chemotherapy.

Interleukin-2 (IL-2)

IL-2, a lymphokine produced by activated T cells (Th1), plays a pivotal role in immune modulation, enhancing the growth of activated T cells, the proliferation of lymphoid cells, and the migration of lymphocytes from the peripheral blood. Anti-tumour activity of IL-2 includes the capacity to lyse fresh tumour cells, the regression of distant metastases in murine models, and the in vivo release of other members of the cytokines family.

IL-2 has been widely applied in the management of patients with advanced cancer. The systemic administration of high doses of IL-2, alone or in combination with lymphokine-activated killer (LAK) cells, activated ex vivo, may induce objective responses in a small proportion of patients with renal cell carcinoma (5-15%) or metastatic melanoma (<15%). Responses have also been demonstrated in patients with acute myeloid leukaemia. These studies were performed in patients of poor prognosis, with advanced and refractory disease.

IL-2 can be given intravenously at doses from 72 000 to 720 000 IU/kg every 8 hours. Toxicities associated with IL-2 administration include:

♦ Flu-like syndrome

♦ Capillary leak syndrome

♦ Severe hypotension

♦ Arrhythmia

♦ Respiratory distress

♦ Somnolence

♦ Thrombocytopenia

♦ Multi-organ malfunction

♦ Toxic fatalities in up to 10% of patients

In melanoma, administration of IL-2 alters the biodistribution of dacarbazine due to enhanced capillary permeability, resulting in synergy. IFN-a enhances IL-2 lymphocyte proliferation and IFN-a /IL-2 combination therapy is undergoing clinical assessment in patients with renal cell carcinoma and melanoma.

Tumour necrosis factor (TNF)

TNF is an important mediator of the inflammatory response, being involved in stress conditions, cachexia, and endotoxin shock. It is mainly produced by monocytes, activated macrophages, and T cells. It induces the expression of MHC class I and II antigens, as well as adhesion molecules responsible for leukocyte migration and accumulation.

TNF (mainly TNF-, has been used in various clinical trials, mostly in patients with advanced melanoma and sarcoma. Results have been disappointing, with <5% response rate. Loco-regional administration (intraperitoneally, intravesically, intralesionally) seems more promising, but its clinical use is limited by the severe side-effects which include:

♦ Thrombocytopenia

♦ Hepatotoxicity

♦ Cytochrome P450 depression

♦ Transient impairment of renal function

♦ Central nervous system toxicity, especially in the elderly

Local administration of rTNF and of TNF encapsulated liposomes could be used in the future to circumvent the problems of toxicity.

Data show synergy between TNF and conventional chemothera-peutic agents such as cyclophosphamide, doxorubicin, and cisplatin. TNF may reverse cisplatin resistance. On the other hand, cisplatin and cyclophosphamide may act as biological modulators by increasing TNF binding to the cell surface.

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