Modelo Entidad – Relación

The choice of the appropriate treatment after the diagnosis of a tumor, is probably one of the most critical problems. There are numerous factors that contributing to the choice of the best treatment i.e.:

the type of cancer, its stage, the presence of metastasis, the age and the health conditions of the patient.

The five traditional methods are surgery, radiotherapy, photodynamic therapy, immunotherapy and chemotherapy. Surgery, radiotherapy and photodynamic therapy are often used for the treatment of locally confined tumors, whereas chemotherapy and immunotherapy are systemic methods. A combination of these strategies is often possible.

1.2.1. Surgery

Surgery is a generally used approach in the case of tumor confined in a specific region. Such method may provide good chances of recovery especially in absence of metastasis. The amount of tissue that can be surgically removed depends on the size of the tumor and the presence of metastasis.

If a person presents a predisposition to a specific form of cancer, it is possible to intervene in a preventive manner. For example, a genetic alteration of the BRACA/1 and BRACA/2 genes predisposes to the onset of ovarian carcinoma and therefore the removal of the ovaries represents a precautionary measure [2]. During diagnostic or staging surgery, tissue samples can also be removed to identify the benign or malignant nature of the tumor by biopsy.

If it is not possible to remove the whole tumor, the first objective of the intervention is to remove as much tumor as possible, in order to make radio- or chemo-therapy treatments (adjuvant therapy) more effective. In some cases, it can also be used a reverse approach (neoadjuvant therapy).

1.2.2. Radiotherapy

Radiotherapy uses ionizing radiation, usually X-rays, to destroy cancer cells by irradiating the mass of the cancerous tissue. The radiations used can be emitted by radioactive substances such as iodine or cobalt (¹³¹I or ⁶⁰Co) or produced by specific devices (linear accelerators) [2]. Thanks to the high energy and the ability to cross cancer cells, X-rays can heavily damage the DNA. The goal of radiotherapy is the induction of severe alterations in the DNA of the cell, which will die since its functionality is compromised. During the therapy, some healthy cells can be affected by the radiation.

However, since such cells are not affected by anomalies in repair mechanisms of the DNA or apoptosis, they have a better resistance toward any suffered damage. The duration and overall dose of treatment depend on the type, size and location of the tumour in the body. Once the appropriate overall therapeutic dose has been determined, the planning of the therapeutic treatment (through a single or repetitive fractions) will be established.

1.2.3. Photodynamic therapy (PDT)

Photodynamic therapy (PDT) has been used since the 1990s and utilize light irradiation to contrast the skin, lung, bladder, prostate, urinary tract, esophagus and ophthalmic neoplasms in the case of localized and not deep-rooted tumours [16]. The PDT utilizes photo-sensitizers, or molecules capable

Light source Tumor

Photosensitizer

1) Administration of photosensitizer 2) Radiation of Light 3) Induction of Apoptosis or Necrosis ROS

Light source Tumor

Photosensitizer

1) Administration of photosensitizer 2) Radiation of Light 3) Induction of Apoptosis or Necrosis ROS

Light source Tumor

Photosensitizer

1) Administration of photosensitizer 2) Radiation of Light 3) Induction of Apoptosis or Necrosis ROS

Light source Tumor

Photosensitizer

1) Administration of photosensitizer 2) Radiation of Light 3) Induction of Apoptosis or Necrosis ROS

of absorbing visible light at an appropriate wavelength interval, to produce the cytotoxic ROS (Reactive Organic Species) which eventually lead the death of tumour cells by apoptosis and necrosis.

This technique allows a precise spatio-temporal control of the treatment, which can also be repeated.

The photo-sensitizer is activated only in the irradiated areas and theoretically induces the destruction of the diseased tissue without causing serious damage to healthy one. This technique also allows the treatment of the not surgically operable areas.

The first FDA approved photosensitizer was Photofrin, consisting of a mixture of dimers and oligomers of porphyrin type units. Thereafter, a second and third generation compounds were developed and coupled with a variety of biological targeting vectors [16]. In the case of porphyrins, it is possible to exploit their fluorescent and phosphorescent emissions, to define the limit between the diseased and the healthy tissues. This technique is also useful for the tumor imaging and the so-called "guided surgery".

The biomedical research are now looking for a possible therapeutic use of the photochemistry mediated by metal complexes on the basis of two different points of view. In one case, starting from a coordinated saturated complex one or more coordination sites will be made vacant allowing the interaction of the metal centre with biomolecules. Alternatively, the biologically active fragment will be constituted by the released ligand. In any case, the irradiation with light will cause the transformation of the pro-drug (stable in the dark) in the active species [16].

1.2.4. Immunotherapy

The goal of the biological therapy or immunotherapy is the increase of the body's ability to identify and destroy cancer cells and repair the cells damaged during the treatment [2].

For this purpose, the following techniques are used:

• Interferons and cytokines: molecules used by the cells of the immune system to communicate each other. Their use can stimulate in some types of cells their immune system and increase their activity level.

• Monoclonal antibodies: proteins produced by some white blood cells that assist the immune system in identifying microbes or malignant cells and then destroying them. Several monoclonal antibodies could selectively bind some proteins present on the surface of tumor cells, marking them as foreign and making them easily identifiable and therefore attackable by the immune system.

• Gene therapy: introduction into the cells of DNA fragments containing genes encoding specific functions. This introduction can be done for example in the cells of the immune system so that proteins can be coded to increase their performance or within the cancer cells for their identification and destruction.

1.2.5. Chemotherapy

Technically, chemotherapy defines any therapeutic treatment perpetrated by means the use of chemicals, but usually the term is associated with the use of drugs for the treatment of cancer [2].

Chemotherapy, unlike surgery or radiotherapy, is a systemic form of treatment because the drugs used can spread in the body, allowing the neutralization of cancer cells also not under the form of solid tumour (i.e. leukaemia or lymphoma) or metastatic repetitions.

In the best of cases, chemotherapy can be used to eliminate all the cancer cells in the body, but it can also be used to minimize, after surgery, the possibility of regrowth of a tumour or to inhibit the future development of metastasis. If a cure for the disease is not available, you can resort to chemotherapy for palliative purposes or to extend the duration and quality of the life of a person.

The anticancer drugs can be distinguished on the basis of their biological action in:

• Antimetabolites: they intervene by blocking a particular metabolic pathway or interfering with the functionality of specific enzymes.

• Alkylating and coordinating agents: they modify the structure of the DNA bases by alkylating (or coordinating) them. After this kind of modification some important functions of the cell can be alterated and cause:

o An excessive DNA fragmentation promoted by the enzymes responsible for the repair of the alterations caused by the alkylating (or coordinating) agent.

o Incorrect coupling of DNA bases.

o Formation of permanent cross-links between the two DNA strands preventing their separation in the replication process.

• Inhibitors of topoisomerases: are a class of enzymes important for the regulation of DNA metabolism.

• Mitotic inhibitors.