The term cancer refers to a malignant tumour. Cancer cells can manifest, in greater or lesser degree, uncontrolled proliferation, invasiveness, the ability to metastasize and/or infiltrate normal tissues and loss of function due to lack of the capacity to differentiate. Benign tumours manifest only uncontrolled proliferation.
Pathology
The two main alterations in DNA underlying cancerous change in a cell are (1) mutation/inactivation of tumour suppressor genes and (2) mutation/activation of proto-oncogenes . Proto-oncogenes are genes that normally code for the growth factor-induced and apoptotic pathways, and thus control the cell cycle and cell proliferation. Oncogenes code for cancerous changes. The development of cancer, however, is a multistage process, involving not only more than one genetic change, but also other non-genetic factors (hormonal effects, presence of carcinogens) that increase the likelihood that the mutation(s) will result in cancer. The formation of new blood vessels (angiogenesis) is required for the growth of the tumour, the infiltration of cancer cells into nearby tissue and their metastasis to other organs.
Most anticancer drugs are cytotoxic, i.e. they damage or kill cells; they do not affect the underlying pathogenetic mechanisms, namely the changes in growth factors and/or their receptors, in the cell cycle and apoptotic pathways, in telomerase expression or in tumour-related angiogenesis. Most are mainly antiproliferative, acting primarily on dividing cells ( Fig. 33.1 ) and have no specific inhibitory effect on invasiveness, the loss of differentiation or the tendency to metastasize. As these cytotoxic drugs inhibit cell proliferation, they will also affect rapidly dividing normal cells. Therefore they can depress the bone marrow, impair healing, depress growth, cause sterility and hair loss and be teratogenic; most cause nausea and vomiting and detrimental effects on the mucous lining of the gastrointestinal (GI) tract.
There are also now many new immunotherapeutic approaches to the treatment of cancers that use the body’s own immune system to attack cancer cells. Other new approaches include targeting receptor mechanisms upregulated in cancer cells and targeting these with biologics ( Table 33.1 ).
| Class of drug | Drug | Mechanism of action | Use | Important side effects |
|---|---|---|---|---|
| Alkylating agent | Cyclophosphamide | Pronounced effect on lymphocytes Immunosuppressant Intrastrand cross-linking of DNA | Haematological malignancy | N&V Bone marrow depression Haemorrhagic cystitis |
| Alkylating agent | Procarbazine | Inhibits DNA and RNA synthesis Interferes with mitosis | Hodgkin’s disease | Hypertension Flushing reaction |
| Platinum compound | Cisplatin | Intrastrand cross-linking of DNA | Solid tumours (especially testes and ovary) | Nephrotoxic Severe N&V |
| Antimetabolite | Fluorouracil | Inhibition of DNA synthesis | Basal cell carcinoma | Gastrointestinal upset Myelotoxicity |
| Antimetabolite | Cytarabine | Pyrimidine analogue—inhibits DNA polymerase | Acute myeloid leukaemia | Gastrointestinal upset Myelotoxicity |
| Cytotoxic antibiotic | Doxorubicin | Inhibits DNA and RNA synthesis, through interference with topoisomerase II | Bladder cancer | N&V Myelosuppression Hair loss Cardiotoxic in high doses |
| Vinca alkaloids (mitotic inhibitor) | Vincristine | Bind to tubulin and inhibit its polymerization, causing arrest at metaphase inhibiting mitosis | Haematological malignancy | Mild myelosuppression Neurotoxic → paraesthesia and weakness Abdominal pain |
| Mitotic inhibitor | Etoposide | Inhibits DNA synthesis by action on topoisomerase II Inhibits mitochondrial function | Haematological malignancy | Vomiting Alopecia Myelosuppression |
| Monoclonal antibody | Rituximab | Binds to CD20 protein → lyses B lymphocytes | Lymphoma | Hypotension Chills and fever Hypersensitivity reaction |
| Monoclonal antibody | Trastuzumab (Herceptin) | Binds to oncogenic protein human epidermal growth factor receptor 2 (HER2) | Breast cancer that overexpress HER2 | |
| Protein kinase inhibitor | Imatinib | Inhibits oncogenic cytoplasmic kinase ( BCR/ABL ) & platelet-derived growth factor | Chronic myeloid leukaemia | Gastrointestinal upset Headaches Rashes (can get resistance) |
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