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In this essay we will discuss about the drugs that are used for the treatment of cancer.
Essay # 1. Cytotoxic Drugs:
The aim of chemotherapy of malignant disease is to kill the malignant cells without any harm to normal cells. Unfortunately, the metabolic process of the malignant cells and normal cells is so very similar or even the same, that cytotoxic drug also kill/damage the normal cells.
The cytotoxic drugs mainly act on rapidly dividing cells by interfering the functions of DNA and RNA. DNA is the vital component of the cell nucleus and is concerned with the cell division (mitotic phase). DNA contains the code, which determines the type of protein to be manufactured by RNA in the cytoplasm and thus ultimately the cell functions. The cells, which do not divide, are very resistant to chemotherapy.
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Although the individual cytotoxic drug has its own toxicity, the commonly encountered side effects with cytotoxic drugs, in general, are on the cells of bone marrow, the lymphatic system and lining of the intestinal tract, which have a high rate of turnover. These result in nausea and vomiting, bone marrow suppression (vincristine and bleomycin exceptions) and alopecia.
Most cytotoxic drugs are teratogenic and should not be given during pregnancy, especially during the first trimester. Cytotoxic drugs fall into a number of classes, each with characteristic antitumour activity, sites of action, and toxicity.
These include:
i. Alkylating drugs
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ii. Antimetabolites
iii. Plant alkaloids
iv. Platinum-containing drugs
v. Cytotoxic antibiotics
vi. Miscellaneous cytotoxic drugs.
i. Alkylating Drugs:
These are chemically very active drugs, which are among the most widely used in cancer chemotherapy. They act by damaging DNA in the cell nucleus (cause DNA cross-linking and strand breaks), thus interfering with cell replication. Most alkylating drugs are cytotoxic to resting and dividing cells.
In addition to the side-effects common to many cytotoxic drugs, there are two problems associated with their prolonged usage. Firstly, they may cause irreversible sterility. Secondly, prolonged use of these drugs, particularly when combined with extensive radiation, is associated with a marked increase in the incidence of acute non-lymphocytic leukemia.
Chlormethine (mustine) is a very toxic drug and is now much less used in Hodgkin’s disease. Nausea and vomiting and bone marrow depression usually affecting the white cells and platelets are common side effects.
Cyclophosphamide is inactive until metabolized by the liver into cytotoxic metabolites. It is widely used in the treatment of chronic lymphocytic leukemia, the lymphomas, and solid tumors in combination with other cytotoxic drugs.
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Depression of bone marrow and loss of hair are common side effects. A urinary metabolite, acrolein, can cause hemorrhagic cystitis, which is a very serious complication and can be avoided by giving a high fluid intake or combining it with mesna. Mesna reacts specifically with the urinary metabolite, preventing toxicity.
Ifosfamide is related to cyclophosphamide and is given intravenously. It is less damaging to the bone marrow, but more likely to damage the kidneys, bladder and CNS. Mesna is routinely given with it to reduce hemorrhagic cystitis. It is contraindicated in hepatic impairment.
Chlorambucil is commonly used to treat chronic lymphocytic leukemia (drug of choice), the indolent non-Hodgkin’s lymphomas, Hodgkin’s disease and ovarian cancer. Side effects, apart from bone marrow depression, are uncommon.
Chlorambucil is one of few cytotoxic drugs which are used continuously orally on an outpatient basis. The only contraindication to its use is rare widespread rashes which can even lead to toxic epidermal necrosis.
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Melphalan is particularly used to treat myeloma and occasionally solid tumours and lymphomas. It is a powerful depressant of white cells and platelets and is usually given orally for a week, with further courses at intervals of 4-6 weeks monitored by blood count.
Busulfan is used almost exclusively to treat chronic myeloid leukaemia where it has a selective depressant action on abnormal white cells.
Busulfan causes myelosuppression which may result in irreversible bone marrow aplasia, hence treatment requires frequent blood counts. Hyperpigmentation of the skin and fibrosis of lungs are other side effects.
Lomustine is used mainly to treat Hodgkin’s disease and certain solid tumours. Bone marrow depression may occur which is delayed and the drug is given orally at intervals of 4-6 weeks. Apart from bone marrow depression, nausea and vomiting are common.
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Carmustine has similar activity and toxicity to lomustine and is mainly used intravenously to treat myeloma, lymphoma and brain tumours. Renal damage and delayed pulmonary fibrosis may occur.
Estramustine is a combination of an estrogen and chlomethine (mustine). The drug concentrates in tissues that have estrogen receptors and both the estrogen and the cytotoxic chlormethine attack the cancer cell.
It is given by mouth in some cases of prostate cancer where it has both an antimitotic effect and (by reducing testosterone concentration) a hormonal effect. Unlike many other cytotoxic drugs estramustine does not destroy the DNA.
Estramustine causes gynecomastia because of the estrogenic effect, and heart and liver toxicity. It is contraindicated in heart and liver disease, and in patients with peptic ulcer.
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Thiotepa is usually used as an intra-cavity drug for the treatment of malignant effusions or bladder cancer. Occasionally, it can be used to treat breast cancer, but requires IV administration.
ii. Antimetabolites:
These are drugs which chemically have a similarity to the naturally occurring substances used by the cells for their metabolic processes. They, thus, become incorporated into nuclear material or combine with vital cellular enzymes and because they cannot be metabolized, the normal cellular division does not take place.
Many antimetabolites resemble the purines or pyrimidine’s, which are the building blocks of DNA. They become incorporated in growing strand of DNA, interrupting replication. Their greatest toxicity occurs in tissues that are actively replicating, e.g. GI mucosa, hematopoietic cells.
Methotrexate is similar in structure to folic acid and inhibits the enzyme dihydrofolate reductase, essential for the synthesis of purines and pyrimidines. It is given orally, intravenously or intrathecally. It is excreted by the kidneys and should be used with caution in renal impairment.
Methotrexate is used as maintenance therapy for childhood acute lymphoblastic leukaemia. It is also used in choriocarcinoma, non- Hodgkin’s lymphoma and a number of solid tumours. Intrathecal methotrexate is used in meningeal cancer or lymphoma.
In certain types of malignant disease, a large and potentially lethal dose of methotrexate is given, which is followed 24 hours after by folinic acid to reverse the action of methotrexate. This method is known as folinic acid rescue.
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Methotrexate in low doses is used as immunosuppressant in rheumatoid arthritis and psoriasis. Bone marrow depression, liver damage, mouth ulceration (mucositis) and rarely pneumonitis may occur. Methotrexate is contraindicated in significant renal and severe hepatic impairment.
Mercaptopurine structurally resembles adenine and hypoxanthine and prevents cell division by competing with them. It is almost exclusively used for the maintenance therapy of acute leukaemia. Azathioprine, a derivative of mercaptopurine is used as an immunosuppressant in a number of autoimmune diseases, when corticosteroid therapy is ineffective. Side effects include depression of normal white cells. Hepatic cholestasis has also been observed.
Tioguanine is given orally to induce remissions in acute myeloid leukaemia. It is excreted by kidneys and should be used cautiously in renal impairment. Fluorouracil is pyrimidine antagonist which is given orally or intravenously to treat a number of solid tumours, including GIT cancers and breast cancer. It is commonly used with folinic acid in advanced colorectal cancer. It can also be applied locally in certain malignant and premalignant skin lesions. Toxicity is unusual, but may include myelosuppression, mucositis and rarely a cerebellar syndrome.
Cytarabine is pyrimidine antagonist and is mainly used to induce remissions in acute myeloblasts leukaemia. It is a potent myelosuppressant and treatment is guided by periodic blood counts. Raltitrexed blocks one of the enzymes involved in DNA synthesis, namely thymidylate synthetase. It is given intravenously for palliation of metastatic colorectal cancer, when drugs such as fluorouracil cannot be used. It is generally well tolerated but can cause gastrointestinal side effects and myelosuppression. It should be used cautiously in hepatic and renal impairment.
Fludarabine is an adenosine monophosphate analog that is used for B-cell chronic lymphocytic leukaemia, when treatment with an alkylating drug has failed. Though well tolerated, fludarabine may cause myelosuppression and immunosuppression. Gemcitabine is a nucleoside analog that is used for palliative treatment of locally advanced or metastatic non-small cell lung and pancreatic cancer. Though, generally well tolerated but may cause fever, edema, flu-like syndrome and rash. It should not be used concurrently with radical radiotherapy.
iii. Plant Alkaloids:
These are naturally occurring nitrogenous bases. Most inhibit cell division through inhibition of mitotic spindle formation.
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Vinca Alkaloids:
Vinblastine, vincristine, and vindesine are the alkaloids derived from periwinkle plant. Vinca alkaloids act by interfering with the assembly of DNA proteins during mitotic phase and thus the cell division does not occur. Vinca alkaloids are used to induce remissions in acute leukaemia and to treat lymphomas and some solid tumours, e.g. breast and lung cancer. Vinorelbine, a semisynthetic vinca alkaloid, is used in advanced breast cancer when anthracycline antibiotics are ineffective and in advanced non-small cell lung cancer.
Vinca alkaloids are highly toxic and are associated with neurological manifestations such as peripheral or autonomic neuropathy which may result in peripheral paraesthesia and loss of deep tendon reflexes, abdominal pain and constipation. Leucopenia (vincristine causes negligible myelosuppression) and irreversible alopecia is common. Extravasation causes severe local irritation and local tissue necrosis.
Etoposide is related to podophyllin, an extract of mandrake. It prevents cell division and is particularly useful in small cell carcinoma of the bronchus, the lymphomas and testicular cancer. Myelosuppression is the major dose-limiting toxicity.
Taxanes- Paclitaxel (Taxol) and Docetaxel (Taxotere) are obtained from yew. They inhibit cell division in the mitotic phase. They are highly toxic and given by IV infusion in advanced ovarian cancer and for secondary treatment of breast cancer, when other regimes have failed.
Premedication with dexamethasone and H1 and H2 blockers is required to prevent hypersensitivity reactions. Myelosuppression, peripheral neuropathy, arthralgias and arrhythmias are important side effects.
Irinotecan and topotescan are derivatives of an extract from tree bark and are chemically related to taxanes. They inhibit cell division by inhibiting topoisomerase I, an enzyme involved in DNA replication. They are given by IV infusion.
Irinotecan is indicated in metastatic colorectal cancer when treatment containing fluorouracil has failed. Topotescan is indicated in metastatic ovarian cancer when other therapies have failed. Side effects include dose-limiting myelosuppression, delayed diarrhea and asthenia.
iv. Platinum-Containing Drugs:
These drugs prevent cell division by a direct action on the DNA itself, causing single and double-strand breaks in DNA. Cisplatin has an alkylating action. It is effective in a number of solid tumours, particularly in ovarian cancer and testicular teratoma. It is a highly toxic drug.
Side effects include severe nausea and vomiting, nephrotoxicity, myelotoxicity, ototoxicity, peripheral neuropathy, and hypo- magnescemia. Carboplatin, a derivative of cisplatin, is equally effective in ovarian cancer. It is also active in small cell lung cancer. It is better tolerated than cisplatin, but is more myelsuppressive. Oxaliplatin is effective in colorectal cancer and its use is associated with a sensory neuropathy.
v. Cytotoxic Antibiotics:
Cytotoxic antibiotics inhibit cell division in several ways; by binding to the DNA, by inhibiting the adjacent DNA nucleotides interrupting DNA replication and transcription to cause strand breaks. They act as radiomimetics and simultaneous use of radiotherapy should be avoided. Cytotoxic antibiotics, in addition to the usual toxicity of cytotoxic drugs (e.g. nausea and vomiting, myelosuppression, mucositis and alopecia), are associated with cardiomyopathy consisting of intractable congestive heart failure and arrhythmias.
Doxorubicin (adriamycin) is the most successful and probably the most widely used cytotoxic antibiotics in acute leukaemias, lymphomas and a variety of solid tumours. It is also given by bladder instillation. A liposomal formulation is indicated for Kaposi’s sarcoma in AIDS patients. Doxorubicin is rapidly taken up by all tissues except brain, highest concentrations being found in thyroid, liver and heart. The drug is largely excreted by the biliary tract.
Mitoxantrone and epirubicin are structurally related to doxorubicin and are useful in the treatment of a variety of cancers. The incidence of adverse effects is relatively low and can be used on an outdoor basis.
Idarubucin is more rapidly taken up in cells than doxorubicin and may replace it in the treatment of acute leukaemias and advanced breast cancer. It can also be given by mouth.
Daunorubicin has also similar properties to those of doxorubicin and is used to treat acute leukaemias and Kaposi’s sarcoma in AIDS patients. Mucositis is dose-limiting toxicity.
Bleomycin has a relatively weaker anticancer activity and is used in combination to treat lymphomas and testicular cancers.
Unlike other anticancer drugs, bleomycin does not depress the bone marrow. Common side effects include dermatological toxicity, hypersensitivity reactions and progressive pulmonary fibrosis which may be fatal. Since, the drug is mainly excreted unchanged by the kidneys; it should be used with caution in renal impairment.
Mitomycin alkylates DNA and has actions like alkylating drugs. It is given intravenously to treat upper GIT and breast cancers and superficial bladder tumours (bladder instillation).
Mitomycin causes delayed bone marrow toxicity and therefore, it is usually administered at weekly intervals. Prolonged use may cause permanent bone marrow damage, lung fibrosis and renal damage.
vi. Miscellaneous Cytotoxic Drugs:
There are more than one dozen drugs of diverse chemical structure, which are used as a second line of treatment and/or as combination therapy in most forms of malignant disease.
Crisantaspase is the enzyme asparaginase which causes cessation of protein synthesis and cellular death. It is exclusively used for acute lymphocytic leukaemia. Adverse effects are common and include anaphylaxis, nausea, vomiting, CNS depression and liver function and blood lipid changes.
Dacarbazine is mainly used in treating melanomas and in combination therapy in Hodgkin’s disease. It is highly irritant and is given very slowly intravenously. Adverse effects are severe bone marrow depression and intense nausea and vomiting.
Hydroxycarbamide (Hydroxyurea) is an orally active drug and is used mainly for chronic myeloid leukemia. It can also be used in polycythemia (the usual treatment is venesection). Reversible myelosuppression is the major side effect. GIT and cutaneous disturbances occasionally occur.
Procarbazine is an oral agent that inhibits DNA, RNA, and protein synthesis. It is most often used as a combination therapy (MOPP — mustne, vincristine, procarbazine and prednisolone) in Hodgkin’s disease. Toxic effects include nausea, myelosuppression and a hypersensitivity rash preventing further use of the drug. It is a mild monoamine oxidase inhibitor and causes disulfiram-like reaction with simultaneous ingestion of alcohol.
Drugs for Cytotoxic Induced Side Effects:
i. Antiemetics:
One of the common disadvantages of chemotherapy is nausea and vomiting. Nausea and vomiting depends on individual patient susceptibility and on the drug being administered. Many patients will respond to pretreatment with oral phenothiazines, metoclopramide and dexamethasone.
ii. 5-Hydroxytriptamine (Serotonin, 5-HT) Antagonists:
A specific 5-HT3 antagonist is a drug of choice for patients at a high risk of emesis with most severely cytotoxic emetic drugs, e.g. cisplatin, or when other antiemetic therapies are ineffective. It is believed that potent cytotoxic emetic drugs stimulate the 5-HT3 receptors in GIT and brain stem. Granisetron or ondansetron or tropisetron (5-HT3 antagonists) combined with dexamethasone are most effective in controlling early emesis of cytotoxic drugs. The 5-HT3 antagonists may be less effective for the control of delayed emesis.
iii. Mucositis (Mouth Ulceration):
Mucositis is due to the direct effect of cytotoxic drugs on the mucous membrane of the mouth and also due to general suppression of immunity (myelosuppression) which encourages the infection.
Fall in white blood cell count may result in candidal (fungus) infection of the mouth which can be treated by nystatin oral suspension or fluconazole and chlorhexidine (corsodyl) mouth wash.
Methotrexate induced mucositis can be counteracted by folinic acid or levofolinic acid. If ulceration develops, the pain can be relieved by a local anaesthetic benzydamine oral rinse.
iv. Bone Marrow Suppression (Myelosuppression):
Cytotoxic drugs except vincristine and bleomycin cause bone marrow suppression. This usually occurs after 7-10 days but may be delayed. Giving bone marrow growth factors can minimise the myelosuppression. These are recombinant human granulocyte- colony stimulating factor (rhG-CSF). Filgrastim or lenograstim increases the production of neutrophils.
Molgramostim (recombinant human granulocyte macrophase-colony stimulating factor) stimulates the production of all granulocytes and monocytes.
v. Alopecia:
Reversible hair loss is a common complication particularly with doxorubicin, etoposide and ifosfamide. No pharmacological methods are available to prevent this complication.
vi. Reproductive Functions:
Most cytotoxics may cause permanent sterility in man and reversible amenorrhoea in women. They are teratogenic and should not be administered during the first trimester.
Essay # 2. Hormones and Hormone Antagonists:
Hormonal therapy has an important role in the treatment of cancer because it causes tumour regression in some cancers. Unlike cytotoxic drugs, it lacks direct cytotoxicity. Hormonal treatments are not curative, but may provide excellent palliation of symptoms, sometimes for a period of years.
Corticosteroids:
Prednisolone, a synthetic glucocorticoid, is widely used in malignant disease. It has a marked antitumour action in acute lymphoblastic leukaemia, Hodgkin’s disease and the non-Hodgkin lymphomas. It is also useful in causing tumour regression in hormone-responsive breast cancer. It is a part of palliative care in end-stage malignant disease as it lifts the patient’s mood and produces a sense of well-being.
Sex Hormones:
Sex hormones are useful in providing remissions in selected patients with the metastatic breast, prostate, and endometrial cancer and renal cell carcinoma.
Estrogens:
Estrogens are now rarely used, although diethylstilbestrol (synthetic estrogen) and its prodrug (fosfestrol) are occasionally used in prostate cancer and ethinylestradiol for breast cancer.
Progestogens:
Medroxyprogesterone and megestrol acetate are the most popular progestogens, which are used orally for endometrial cancer, renal cell carcinoma and as second or third- line treatment for breast cancer. They have also been used for the treatment of cachexia (a profound and marked state of constitutional disorder; general ill health and malnutrition) associated with AIDS. Side effects are minor and include occasional nausea, weight gain and fluid retention.
Androgens:
Androgens are occasionally still used as second-or third-line treatments for breast cancer. However, their use is associated with many problems and contraindications.
Sex hormones, now more or less, are seldom indicated in the treatment of breast and prostate cancer, because the safer approach is to block the actions of sex hormones (estrogens and testosterone) at their receptors, which has been made possible with the availability of hormone antagonists.
Hormone Antagonists:
Hormone antagonists are oestrogen receptor antagonists and androgen receptor antagonists as well as the drugs which prevent the production of estrogens and testosterone and have virtually replaced the sex hormones in the treatment of hormone-responsive breast cancer and prostate cancer. In general, hormone antagonists have few serious adverse effects.
Breast Cancer:
Tamoxifen is a non-steroidal estrogen receptor antagonist. It is the adjuvant hormonal treatment of choice, particularly in estrogen dependant breast cancer.
Tamoxifen has also been reported to reduce the incidence of breast cancer in normal women at high risk.
Tamoxifen is also prescribed for anovulatory sterility, when the drug is taken on days 2, 3, 4 and 5 of the menstrual cycle.
Side effects are mild and include occasional nausea, hot flushes, fluid retention and a hormone flare (bone pain and hyercalcemia) which subsides within 7-10 days. Tamoxifen is contraindicated in breast-feeding and before planned pregnancy.
Long-term use of tamoxifen carries the risk of endometrial cancer. Toremifene, also an estrogen receptor antagonist, is used to treat hormone-dependent metastatic breast cancer in postmenopausal women. Aromatase inhibitors inhibit the conversion of androgens to estrogens in the peripheral tissues.
The first- and second-generation aromatose inhibitors inhibit the steroid synthesis in adrenals and require corticosteroid replacement therapy. Third generation aromatose inhibitors are better tolerated and are more specific since they do not suppress adrenal Cortisol production and are used in the treatment of advanced hormone-responsive breast cancer in postmenopausal women.
Two non-steroidal agents, anastrazole and letrozole and one steroidal agent, exemestane are the third generation aromatase inhibitors that have been found to be active in hormone-sensitive breast cancer. They may be slightly more effective than tamoxifen. Side effects are usually minimal and include hot flashes and night sweats, but thrombotic episodes may occur.
Prostate Cancer:
Prostatic carcinoma with metastases, usually, responds to hormonal treatment which deprives the cancer of androgen. With the availability of androgen receptor antagonists and better understanding of gonadotrophin-releasing hormone (GnRH), the treatment is generally carried out by drugs instead of bilateral sub-capsular orchidectomy. GnRH fgonadorelin) causes the release of LH and FSH from the anterior lobe of the pituitary gland. If, however, GnRH is given as a continuous treatment, it shuts down the production of luteinising hormone (LH) and therefore of testosterone.
GnRH Agonists:
Leuprolide and gosereljn are the commonly used GnRH synthetic analogues as monthly SC depot injection for the treatment of metastatic prostate cancer. They cause initial stimulation of LH release by the pituitary, which in turn causes testerone secretion from the testes; this is followed by inhibition of LH release release, thus effectively shutting down testerone production.
During the first 1 to 2 weeks of therapy a number of patients develop a tumour “flare” which may cause spinal cord compression or increased bone pain. To avoid initial flare in tumour symptoms, anti-androgen treatment is started 3 days before GnRH agonists and continued for 3 weeks. Other side effects of GnRH analogues are similar to those of orchiectomy.
Androgen Receptor Antagonists:
Flutamide and bicalutamide block the actions of androgens at their receptor sites. They are used alone or with other treatment for prostate cancer. They should be prescribed before treating patients with GnRH agonists to cover the tumour “flare” which may occur with GnRH analogues, due to an initial release of testosterone from the testes before shutting them down.
Essay # 3. Immunotherapy:
Like hormonal therapy, immunotherapy provides an improvement in survival compared to chemotherapy alone in metastatic disease. They are, in fact, immunosuppressant which affects the immune response involved in cellular growth, cell proliferation and survival. Immunotherapeutic agents may be selective or nonspecific. Selective immunotherapy include biologies consisting of monoclonal antibodies, most of which are partially humanized.
Trastuzumab is a monoclonal antibody protein that binds to and inactivates a receptor called human epidermal growth factor receptor 2 (HER2). HER2 is overexpressed in many cancers, especially breast, lung, ovarian and prostate, and overexpression of HER2 is associated with a poor prognosis.
Trastuzumab is used in patients with metastatic breast cancer with paclitaxel in whom other approaches have failed. Side effects include IV infusion-related symptoms, hypersensitivity reactions and delayed GI upsets, and cardiotoxicity.
Rituximab and alemtuzumab are both monoclonal antibodies that block the lysis of B lymphocytes. Rituximab is used to treat diffuse large B cell non-Hodgkin’s lymphoma in conjunction with other chemotherapeutic drugs an advanced follicular lymphoma that is resistant to other chemotherapies.
Alemtuzumab is used for patients with chronic lymphocytic leukemia who have failed to respond to other treatments. Both the drugs can give rise to IV infusion related adverse effects, which requires prior administration of antihistamines and corticosteroid, especially with rituximab.
Nonspecific Immunotherapy:
Interferon-alpha is used for rare hairy-celled leukemia, chronic myelogenous leukemia and melanoma. Side effects include nausea and vomiting, flu-like symptoms and headaches. Aldesleukin (interleukin-2 prepared using recombinant DNA technology) produces remissions in melanoma and metastatic renal cell carcinoma. It is extremely toxic to several organs, including the thyroid, bone marrow, liver, kidney and brain.
