Anti- CANCER drugs

Dr. Mohammed Abd-Almoneim

Jill liked daytime television chat shows. One morning she watched as a resident doctor explained how common breast cancer was and why women should examine their breasts. Jill had been extremely anxious about the disease and did not want to think about it. Jill decided that she should examine herself and was shocked to discover a hard lump the size of a pea in her right breast. The next day Jill saw the GP. Her mother died of bilateral breast cancer at the age of 39, but her father was alive and healthy aged 65 years. Jill had a sister and a brother aged 35 and 32 years old respectively, both were healthy.

On examination Jill’s GP confirmed the lump in her breast, but she also found a lump in the right axilla. The doctor told her she would need additional tests in the local hospital to make a diagnosis. Jill was referred to the local breast clinic. She is told that she has a clinical TNM stage II tumour and there were two options; to remove part of the breast (breast conserving surgery) or the whole of the breast (total mastectomy). In addition, the local lymph nodes would need to be removed followed by radiotherapy treatment. Jill found this a very difficult decision to make but eventually decided to have a total mastectomy with immediate reconstruction and axillary lymph node clearance.

The pathologist’s report on this tissue confirmed the presence of a stage II infiltrating ductal carcinoma with involvement of a single axillary lymph node. The tumour tissue was tested for hormone receptors and found to be ER and PR positive. She was prescribed long–term tamoxifen. Jill became very depressed after this and found it very difficult to cope with life. However, as a few years went by and she was free of disease she started to return to a level of normality. Five years later she has had no recurrence and she was otherwise fit and well.

Treatment of Cancer• Surgery to remove solid tumors• Radiation to kill cancer cells that have spread to

adjacent local or regional tissues• Chemotherapy to kill cancer cells located

throughout the body

Treatment of cancer

There are three main approaches to treating established cancer: Surgery, Radiation therapy, Chemotherapy

Chemotherapy of cancer presents a difficult problem. In biochemical terms, cancer cells and normal cells are so similar in most respects that it is more difficult to find differences between them.

Surgery Radiation ChemotherapyBreast cancer

Advances in Cancer Chemotherapy Treatment options of cancer:

• Surgery: before 1955

• Radiotherapy: 1955~1965

• Chemotherapy: after 1965

• Immunotherapy, biological therapy and Gene therapy

The treatment of a patient with cancer may aim to:

• give palliation, for relief of unpleasant symptoms such as superior vena cava obstruction from a mediastinal tumor

• induce ‘remission’ so that all macroscopic and microscopic features of the cancer disappear, though disease is known to persist

• cure, for which all the cells of the tumour must be destroyed.

Classifications of Anti- CANCER drugs According to mechanism:

1-Alkylating agents: Example: nitrogen mustard and cyclophosphamide.Mechanism: bind irreversibly to macromolecules in the cell as DNA, RNA

and proteins. 2-Antimetabolites: Mechanism: these are closely related analogues of normal components

intermediary metabolism or DNA synthesis.Example: Methotrexate inhibits folic acid metabolism. 6-mercaptopurine inhibit DNA synthesis.

3-Natural products: A wide range of drugs has been developed from plants, bacteria, yeasts and fungi.

Examples and mechanisms: Mitosis inhibitors: as vincristine . Antibiotics: as actinomycin D. 4-Steroid hormones and antihormones: Examples: prednisolone, tamoxifen and cyproterone acetate. 5-Others: Several drugs have been identified, Mechanism of

action is not fully established but are thought to interact with DNA synthesis or replication. They include , dacarbazine, and cis-platinum.

Alkylating Agents• One of the frightening developments of World

War I was the introduction of chemical warfare. The nitrogen mustards were observed to inhibit cell growth, especially of bone marrow. Shortly after the war, these compounds were investigated and shown to inhibit the growth of cancer cells.

Alkylating AgentsMechanism of Action

• Nitrogen mustards inhibit cell reproduction by binding irreversibly with the nucleic acids (DNA).

• The specific type of chemical bonding involved is alkylation.

• After alkylation, DNA is unable to replicate and therefore can no longer synthesize proteins and other essential cell metabolites.

• Consequently, cell reproduction is inhibited and the cell eventually dies from the inability to maintain its metabolic functions.

Antimetabolites (Folic Acid Antagonist)

Methotrexate （MTX）Mechanism of Action： The structures of MTX and folic acid are

similar. MTX is actively transported into mammalian cells and inhibits dihydrofolate reductase, the enzyme that normally converts dietary folate to the tetrahydrofolate form required for thymidine and purine synthesis.

Hormones• Several types of hormone-dependent cancer

(especially breast, prostate, and endometrial cancer) respond to treatment with their corresponding hormone antagonists.

• Estrogen antagonists are primarily used in the treatment of breast cancer (tamoifen)

whereas androgen antagonists are used in the treatment of prostate cancer (cyproterone acetate).

• Corticosteroids (predinsolone) are particularly useful in treating lymphocytic leukemias and lymphomas.

HormonesAntiestrogen: Tamoxifen• Tamoxifen is the drug of choice in

postmenopausal women with or recovering from metastatic breast cancer. It is most effective in patients who have estrogen receptor-positive tumors.

• Tamoxifen is also used as adjunvctive therapy to oophorectomy to leuprolide or goserelin in premenopausal women with estrogen receptor-positive tumors.

Hormones

Glucocorticoids:• They are integral components of curative

therapy for acute lymphoblastic leukemia, non-Hodgkin’s lymphoma, and Hodgkin’s disease.

• Glucocorticoids have essential roles in the prevention of allergic reaction, vomiting control, relief of intracranial hypertension or spinal cord compression in neurologic complications, and pain relief.

HormonesEstrogens:

• Estrogens inhibit the effects of endogenous

androgens and androgen-dependent metastatic

prostatic carcinoma.

• Cardiac and cerebrovascular complications and

carcinoma of the male breast are potential

adverse effects.

HormonesProgenstins:

• Progestins are useful in the management of

endometrial carcinoma and back-up therapy

for metastatic hormone-dependent breast

cancer.

Problems With Cancer Chemotherapy

• Drug Resistance.

• Drug Toxicity.

Adverse effects:

A- general: Reactions to cancer chemotherapy are

secondary to cell death both in the tumor and in other rapidly dividing cells of bone marrow, gastrointestinal tract, germinal epithelium etc.

1-Nausea and vomiting: related to the direct actions of cytotoxic drugs on the

chemoreceptor trigger zone or secondary to extensive tissue damage as occurs in radiation sickness.

Metoclopramide (antiemetics) and the cannabinoid nabilone can be used to control nausea and vomiting.

2-Alopecia: is a common adverse effect of cytotoxic drugs. Hair re-grows after

the drugs are withdrawn.

4-Hyperuricaemia: Very high levels of plasma uric acid with precipitation

of clinical gout or renal failure may complicate treatment of leukaemias and Iymphomas.

Allopurinol, the xanthine oxidase inhibitor, may be used to prevent gout.

5-Diarrhoea and malabsorption: occur as a result of cytotoxic effects on gut mucosal

cell turnover.

6-Bone marrow depression: The bone marrow is particularly sensitive to cytotoxic

drugs. Neutropenia or thrombocytopenia is common. They result in an increased risk of infection and haemorrhage respectively.

7-Opportunistic infections: occur as a result of neutropenia and

immunosuppressant therapy, which interfere with humoral and cell-mediated responses. Unusual infection with fungi and protozoa in addition to common pathogenic bacteria and viruses occur.

B. Specific adverse effects

• Cyclophosphamide :haematuria, cystitis• Doxorubicin : cardiotoxic, alopecia.• Bleomycin : pulmonary fibrosis.• Methotrexate: marrow suppression,

megaloblastic anaemia. • Vincristine: peripheral neuropathy.• Cisplatinum: Renal damage.

Drug Interactions • With many cytotoxic drugs in use, often in combination, it is not

surprising that adverse interactions occur. More important, however, are the interactions noted between cytotoxic drugs, and non-cytotoxic agents.

• Methotrexate and salicylates: As methotrexate is highly protein bound it is readily displaced from the binding site by aspirin and other salicylates. This may increase the risk of adverse effects of methotrexate. Other acidic drugs which are highly protein bound may show similar effects.

• 6-Mercaptopurine and allopurinol: These two drugs are frequently used together. Allopurinol is a competitive inhibitor of xanthinc oxidase and also inhibits the breakdown of 6-mercaptopurine. The dose of 6-mercaptopurine must be reduced by at least 50% or toxicity ensues. Azathioprine, which is metabolized to 6-mercaptopurine, should also be given in lower doses if used with allopurinol.

Biological therapy• These agents specifically target molecular

anomalies in signal transduction pathways that exist in tumour cells.

• As biological agents target pathways which are more critical to cancer cells than normal cells they are generally less toxic than chemotherapy and in some cases are more effective.

• Example: monoclonal antibodies

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