Cancer Chemotherapy PDF

Cancer chemotherapy Cancer: A disease associated with uncontrolled multiplication and spread within the body of abnormal forms of the body’s own cells. Tumour: local swelling Neoplasm: New growth Localised growth: benign Invasiveness and/or capacity to metastasize: malignant Variability in cance...

Cancer chemotherapy Cancer: A disease associated with uncontrolled multiplication and spread within the body of abnormal forms of the body’s own cells. Tumour: local swelling Neoplasm: New growth Localised growth: benign Invasiveness and/or capacity to metastasize: malignant Variability in cancers but all have the following basic characteristics: Uncontrolled proliferation Local invasiveness Tendency to spread (metastasis) Changes in morphology of the original cell Etiology of cancer Two main alterations underlie cancerous change in a cell. Mutation/inactivation of tumour-supressor genes Mutation/activation of proto-oncogenes Proto-oncogenes normally code for the growth factors and thus control cell cycle and cell proliferation Oncogenes code for cancerous changes Cancer development is a multistage process, involving several genetic and non-genetic changes (hormonal actions, angiogenesis) carcinogen actions that facilitate the possibility of following genetic mutations.  Cell cycle The cell cycle is the sequence of events that a cell goes through from one mitotic division to the next. The cell cycle consists of four major phases: G1, S, G2, and M. For our purpose, we can imagine the cycle as beginning with G1, the phase in which the cell prepares to make DNA by synthesizing histones (proteins found in chromatin). Following G1, the cell enters S phase, the phase in which DNA synthesis actually takes place. After synthesis of DNA is complete, the cell enters G2 and prepares for mitosis (cell division).  Cell cycle Mitosis occurs next during M phase. Upon completing mitosis, the resulting daughter cells have two options: they can enter G1 and repeat the cycle, or they can enter the phase known as G0. Cells that enter G0 become mitotically dormant; they do not replicate and are not active participants in the cycle. Cells may remain in G0 for days, weeks, or even years. Under appropriate conditions, resting cells may leave G0 and resume active participation in the cycle Cancer chemotherapy: The use of drugs to inhibit the rate of growth, or to kill cancerous cells, while having minimal effect upon non-neoplastic host cells. Therapeutic intervention exploits: Striking difference in the accelerated rate of cell division between cancerous and non-cancerous cells. The chemotherapeutic techniques used: Cytotoxic therapy Endocrine therapy Immunotherapy Cytotoxic therapy Most cytotoxic drugs affect DNA synthesis Classified based on their action at a particular site in the process of DNA synthesis within the cancer cell. Cytotoxic drugs are therefore most active against: proliferating cells, normal & malignant, least active against non-dividing cells. Phase specific drugs are only effective at killing cycling cells during specific parts of the cell cycle. Cycle specific drugs kill cycling cells throughout the cell cycle Selectivity of cytotoxic drugs Cytotoxic drugs affect all dividing tissues both normal and malignant. Relative selectivity (marginal) occurs because: In tumours a higher proportion of cells are proliferating than in normal proliferating tissues Normal cells recover from chemotherapeutic damage faster than cancer cells Synchronized cell cycling may promote vulnerability to cytotoxic drugs MAJOR TOXICITIES OF CHEMOTHERAPEUTIC DRUGS Bone Marrow Suppression Chemotherapeutic drugs are highly toxic to the bone marrow, a tissue with a high proportion of proliferating cells. Myelosuppression reduces the number of circulating neutrophils, platelets, and erythrocytes. Loss of these cells has three major consequences: (1) infection (from loss of neutrophils); (2) bleeding (from loss of platelets); and (3) anemia (from loss of erythrocytes). Neutropenia Neutrophils (neutrophilic granulocytes) are white blood cells that play a critical role in fighting infection. In patients with neutropenia (a reduction in circulating neutrophils), both the incidence and severity of infection are increased.  With most anticancer drugs, the onset of neutropenia is rapid and recovery develops relatively quickly. Neutropenia begins to develop a few days after dosing, and the lowest neutrophil count, called the nadir, occurs between days 10 and 14. Neutrophil counts then recover a week or so later. Patients are at highest risk during the nadir. Accordingly, special care should be taken to prevent infection  Neutrophil counts must be monitored. Normal counts range from 2500 to 7000 cells/mm3. If neutropenia is substantial (absolute neutrophil count below 500/mm3), chemotherapy should be withheld until neutrophil counts return toward normal. A lack of neutrophils confounds the diagnosis of infection. Why? Because the usual signs of infection (e.g., pus, abscesses, infiltrates on the chest x-ray) depend on neutrophils being present. In the absence of neutrophils, fever is the principal early sign of infection  Thrombocytopenia Bone marrow suppression can cause thrombocytopenia (a reduction in circulating platelets), thereby increasing the risk for serious bleeding. Bleeding from the nose and gums is relatively common. Bleeding from the gums can be reduced by avoiding vigorous toothbrushing. Drugs that promote bleeding (e.g., aspirin, anticoagulants) should not be used. When a mild analgesic is required, acetaminophen, which does not promote bleeding, is preferred to aspirin Caution should be exercised when performing procedures that might promote bleeding. Intravenous needles should be inserted with special care, and intramuscular injections should be avoided. Blood pressure cuffs should be applied cautiously, because overinflation may cause bruising or bleeding  Anemia Anemia is defined as a reduction in the number of circulating erythrocytes (red blood cells). Although anticancer drugs can suppress erythrocyte production, anemia is much less common than neutropenia or thrombocytopenia. Why? Because circulating erythrocytes have a long life span (120 days), which usually allows erythrocyte production to recover before levels of existing erythrocytes fall too low. If anemia does develop, it can be treated with a transfusion or with erythropoietin (epoetin alfa or darbepoetin alfa), a hormone that stimulates production of red blood cells.  Digestive Tract Injury The epithelial lining of the GI tract has a very high growth fraction, so it is exquisitely sensitive to cytotoxic drugs. Stomatitis and diarrhea are common. Severe GI injury can be life threatening. Nausea and Vomiting Nausea and vomiting are common sequelae of cancer chemotherapy. These responses, which result in part from direct stimulation of the chemoreceptor trigger zone, can be both immediate and dramatic, and may persist for hours or even days. In some cases, discomfort is so great as to prompt refusal of further treatment.  Other Important Toxicities Alopecia Reversible alopecia (hair loss) results from injury to hair follicles. Alopecia can occur with most cytotoxic anticancer drugs. Hair loss begins 7 to 10 days after the onset of treatment and becomes maximal in 1 to 2 months. Regeneration begins 1 to 2 months after the last course of treatment  Reproductive Toxicity The developing fetus and the germinal epithelium of the testes have high growth fractions. As a result, both are highly susceptible to injury by cytotoxic drugs, especially the alkylating agents. These drugs can interfere with embryogenesis. causing death of the early embryo. They may also cause fetal malformation. Risk is highest during the first trimester, and hence chemotherapy should generally be avoided during this time. However, after 18 weeks of gestation, risk appears to be very low  Hyperuricemia Hyperuricemia is defined as an excessive level of uric acid in the blood. Uric acid, a compound with low solubility, is formed by the breakdown of DNA following cell death. Hyperuricemia is especially common following treatment for leukemias and lymphomas (because therapy results in massive cell kill). The major concern with hyperuricemia is injury to the kidneys secondary to deposition of uric acid crystals in renal tubules. The risk for crystal formation can be reduced by increasing fluid intake. In patients with leukemias and lymphomas, in whom hyperuricemia is likely, prophylaxis with allopurinol is the standard of care  Local Injury From Extravasation of Vesicants Certain anticancer drugs, known as vesicants, are highly chemically reactive. These drugs can cause severe local injury if they make direct contact with tissues. Vesicants are administered IV, usually into a central line (because rapid dilution in venous blood minimizes the risk for injury). When a peripheral line is used, administration is by IV push into a freely flowing IV line. Sites of previous irradiation should be avoided. Extreme care must be exercised to prevent extravasation, because leakage can produce high local concentrations, resulting in prolonged pain, infection, and loss of mobility. Severe injury can lead to necrosis and sloughing, requiring surgical débridement and skin grafting. If extravasation occurs, the infusion should be stopped immediately. Because of the potential for severe tissue damage, vesicants should be administered only by clinicians specially trained to handle them safely  The cytotoxic agents constitute the largest class of anticancer drugs. As their name implies, these agents act directly on cancer cells to cause their death. The cytotoxic drugs can be subdivided into eight major groups: (1) alkylating agents eg. Melphalan, cyclophosphamide, chlorambucil, (2) platinum compounds cisplatin (3) antimetabolites Folic antagonists (methotrexate), antipyrimidines (fluorouracil and cytarabine), and antipurines (mercaptopurine) (4) antitumor antibiotics Dactinomycin (actinomycin D), bleomycin and doxorubicin (5) mitotic inhibitors eg vinca alkaloids (vincristine, vinblastine, vinorelbine, taxanes (paclitaxel), (6) topoisomerase inhibitors eg. Etoposide, topotecan (8) miscellaneous cytotoxic drugs eg. Procarbazine, hydroxyurea, crisantaspase, mitotane, amsacrine  Cell-Cycle Phase Specificity Some anticancer agents, known as cell-cycle phase– specific drugs, are effective only during a specific phase of the cell cycle. Other anticancer agents, known as cell-cycle phase–nonspecific drugs, can affect cells during any phase of the cell cycle. About half of the cytotoxic anticancer drugs are phase specific, and the other half are phase nonspecific. Site of action of cytotoxic drugs that act on dividing cells Cell cycle and point of action of phase-specific anti-cancer drugs Alkylating agents eg. Melphalan, cyclophosphamide, chlorambucil, cisplatin Mechanism of action Act via reactive alkyl group that forms covalent bonds with nucleic acids. This leads to cross-linking of the two strands of DNA, thus inhibiting replication or DNA-strand breakage. As a rule, alkylating agents interact with DNA by forming a covalent bond with a specific nitrogen atom in guanine. The consequences of guanine alkylation are miscoding, scission of DNA strands, and, if cross-links have been formed, inhibition of DNA replication  Nitrogen Mustards There are six nitrogen mustards approved for chemotherapy in the United States. They are cyclophosphamide, mechlorethamine, bendamustine, chlorambucil, melphalan, and ifosfamide. Cyclophosphamide. Cyclophosphamide, formerly available as Cytoxan and Neosar, is a bifunctional alkylating agent active against a broad spectrum of neoplastic diseases. Indications include Hodgkin’s disease, non-Hodgkin’s lymphomas, multiple myeloma, and solid tumors of the head, neck, ovary, and breast. Of all the alkylating agents, cyclophosphamide is employed most widely  Nitrosoureas e.g Carmustine The nitrosoureas are bifunctional alkylating agents and are active against a broad spectrum of neoplastic diseases. Cell kill results from cross-linking DNA. Unlike many anticancer drugs, the nitrosoureas are highly lipophilic, and hence can readily penetrate the blood-brain barrier. As a result, these drugs are especially useful against cancers of the CNS. The major dose-limiting toxicity is delayed bone marrow suppression Route of administration:  Melphalan and cyclophosphamide orally and i.v  Chlorambucil orally Clinical uses  Melphalan in myeloma and solid tumours  Cyclophosphamide in leukaemias, lymphomas and solid tumours  Chlorambucil in leukaemias, lymphomas and ovarian tumours Adverse effects: Toxicities Alkylating agents are toxic to tissues that have a high growth fraction. Accordingly, these drugs may injure cells of the bone marrow, hair follicles, GI mucosa, and germinal epithelium. Blood dyscrasias caused by bone marrow suppression— neutropenia, thrombocytopenia, and anemia—are of greatest concern. Nausea and vomiting occur with all alkylating agents. Also, several of these drugs are vesicants, and hence must be administered through a free-flowing IV line.  PLATINUM COMPOUNDS The platinum-containing anticancer drugs—cisplatin, carboplatin, and oxaliplatin—are similar to the alkylating agents and often classified as such. The platinum compounds produce cross-links in DNA, and hence are cell-cycle phase nonspecific.  Cisplatin The drug is approved only for metastatic testicular and ovarian cancers and advanced bladder cancer. Nonetheless, it is used off-label as a component in standard-of-care regimens for lung cancer and head and neck cancer Cisplatin is highly emetogenic; nausea and vomiting begin about 1 hour after dosing and can persist for several days. Other adverse effects include clinically important peripheral neuropathy, mild to moderate bone marrow suppression, kidney damage, and ototoxicity, which manifests as tinnitus and high frequency hearing loss. The drug is given by IV infusion.  Carboplatin The drug’s only approved indications are initial and palliative therapy of advanced ovarian cancer. Unlabeled uses include small cell cancer of the lung, squamous cell cancer of the head and neck, and endometrial cancer. Carboplatin is administered by IV infusion. Anaphylactic reactions have occurred minutes after dosing; symptoms can be managed with epinephrine, glucocorticoids, and antihistamines. Oxaliplatin Actions and Uses Oxaliplatin is approved only for colorectal cancer  ANTIMETABOLITES Antimetabolites are effective only against cells that are active participants in the cell cycle. Most antimetabolites are S-phase specific, although some can act during any phase of the cycle, except G0. To be effective, agents that are S-phase specific must be present for an extended time. There are three classes of antimetabolites: (1) folic acid analogs, (2) pyrimidine analogs, and (3) purine analogs  Folic Acid Analogs Folic acid, in its active form, is needed for several essential biochemical reactions. The folic acid analogs block the conversion of folic acid to its active form. At this time, three analogs of folic acid are used against cancer: methotrexate, pemetrexed, and pralatrexate. Other folate analogs are used to treat bacterial infections (trimethoprim), malaria (pyrimethamine), and Pneumocystis jiroveci pneumonia (trimetrexate).  Methotrexate Mechanism of Action. Methotrexate [Rheumatrex, Trexall] inhibits dihydrofolate reductase, the enzyme that converts dihydrofolic acid (FH2) into tetrahydrofolic acid (FH4). Because production of FH4 is a necessary step in the activation of folic acid and because activated folic acid is required for biosynthesis of essential cellular constituents (DNA, RNA, proteins), inhibition of FH4 production has multiple effects on the cell.  Of all the processes that are suppressed by reduced FH4 availability, biosynthesis of thymidylate appears most critical. Why? Because, in the absence of thymidylate, cells are unable to make DNA. Because cell death results primarily from disrupting DNA synthesis, methotrexate is considered S-phase specific.  Methotrexate Please note, however, that in addition to its S-phase effect, methotrexate has another beneficial action: The fall in thymidine levels caused by methotrexate is a potent signal for inducing apoptosis (programmed cell death). A technique known as leucovorin rescue can be employed to enhance the effects of methotrexate. Some neoplastic cells are unresponsive to methotrexate because they lack the transport system required for active uptake of the drug. By giving massive doses of methotrexate, we can force the drug into these cells by passive diffusion.  Leucovorin rescue However, because this process also exposes normal cells to extremely high concentrations of methotrexate, normal cells are also at risk. To save them, leucovorin (citrovorum factor, folinic acid) is given. Leucovorin bypasses the metabolic block caused by methotrexate, thereby permitting normal cells to synthesize thymidylate and other compounds. Malignant cells are not saved to the same extent because leucovorin uptake requires the same transport system employed for methotrexate uptake, a transport system these cells lack. It should be noted that leucovorin rescue is potentially dangerous: Failure to administer leucovorin in the right dose at the right time can be fatal  Pharmacokinetics. Methotrexate can be administered PO, IM, IV, and intrathecally. The drug is highly polar, and hence a transport system is needed to enter mammalian cells. In cancer cells and normal cells, methotrexate undergoes enzymatic activation to a polyglutamated form. Elimination is primarily renal. Because methotrexate is highly polar, it crosses the blood-brain barrier poorly, except when given in very high doses. To ensure effective levels, intrathecal administration is employed for most CNS cancers.  Toxicity. The usual dose-limiting toxicities are bone marrow suppression, pulmonary infiltrates and fibrosis, and oral and GI ulceration. Death may result from intestinal perforation and hemorrhagic enteritis. Nausea and vomiting may occur shortly after administration. High doses can directly injure the kidneys. To promote drug excretion and thereby minimize renal damage, the urine should be alkalinized and adequate hydration maintained. Methotrexate has been associated with fetal malformation and death. Accordingly, pregnancy should be avoided until at least 6 months after completing treatment.  Resistance. Cancer cells can acquire resistance to methotrexate through five mechanisms: (1) decreased uptake of methotrexate, (2) increased synthesis of dihydrofolate reductase (the target enzyme for methotrexate), (3) synthesis of a modified form of dihydrofolate reductase that has a reduced affinity for methotrexate, (4) increased production of a transporter that pumps methotrexate out of cells, and (5) reduced production of enzymes needed to convert methotrexate to its active (polyglutamated) form.  Therapeutic Uses. Methotrexate is curative for women with choriocarcinoma. The drug is also active against non-Hodgkin’s lymphoma and acute lymphocytic leukemia of childhood.  Purine Analogs The purines—adenine, guanine, are bases employed for biosynthesis of nucleic acids. The purine analogs discussed here are used primarily in the treatment of cancer. They are mercaptopurine, cladribine, clofarabine, fludarabine, nelarabine, pentostatin, and thioguanine. Mercaptopurine Mechanisms of Action and Resistance. Mercaptopurine [Purinethol] is a prodrug that undergoes conversion to its active form within cells. Following activation, the drug can disrupt multiple biochemical processes, including purine biosynthesis, nucleotide interconversion, and biosynthesis of nucleic acids.. Mercaptopurine is S-phase specific.  Pharmacokinetics. Mercaptopurine is administered orally and undergoes erratic absorption. Absorbed drug is distributed widely, but not to the CNS. Therapeutic Uses. The principal indication for mercaptopurine is maintenance therapy of acute lymphocytic leukemia in children and adults. Toxicity. Bone marrow suppression (neutropenia, thrombocytopenia, anemia) is the principal dose-limiting toxicity. Mild hepatotoxicity, manifesting as elevations in bilirubin and liver transaminases  Pyrimidines—cytosine, thymine, and uracil—are bases employed in the biosynthesis of DNA and RNA. The pyrimidine analogs, because of their structural similarity to naturally occurring pyrimidines, can act in several ways: (1) they can inhibit biosynthesis of pyrimidines, (2) they can inhibit biosynthesis of DNA and RNA, and (3) they can undergo incorporation into DNA and RNA, and thereby disrupt nucleic acid function. All of the pyrimidine analogs are prodrugs that must be converted to their active forms in the body. We currently have five pyrimidine analogs: cytarabine, fluorouracil, capecitabine, floxuridine, and gemcitabine  Fluorouracil Fluorouracil [Adrucil] is a fluorinated derivative of uracil. The drug is employed extensively to treat solid tumors. Mechanism of Action. To exert cytotoxic effects, fluorouracil must be converted to its active form, 5-fluoro- 2′-deoxyuridine-5′-monophosphate ( FdUMP). FdUMP inhibits thymidylate synthetase, thereby depriving cells of thymidylate needed to make DNA. Fluorouracil is active only against cells that are going through the cell cycle; it shows some S-phase specificity.  Cytarabine Cytarabine [Cytosar ], also known as cytosine arabinoside and Ara-C, is an analog of deoxycytidine. The drug has an established role in treating acute myelogenous leukemia. Cytarabine is available in two formulations: (1) conventional [Tarabine PFS ] for IV and subQ dosing, and (2) liposomal [DepoCyt] for intrathecal dosing Route of administration Methotrexate, oral, i.v, i.m, i.t Fluorouracil, usually i.v, though oral and topical available Cytarabine, s.c, I.v, and I.t Mercaptopurine, orally Indications: Methotrexate for acute lymphoblastoid leukaemia and non-Hodgkin’s lymphoma;  Fluorouracil for solid tumours and some malignant skin conditions Cytarabine for acute myeloblastoid leukaemia Mercaptopurine as maintenance therapy for acute leukaemias Adverse effects: generalized toxicity Methotrexate not given to patients with significant hepatic or renal impairment Cytotoxic antibiotics eg. Dactinomycin (actinomycin D), bleomycin and doxorubicin Mechanisms of action Several mechanisms of action Dactinomycin inhibits transcription by interfering with RNA polymerase Doxorubicin inhibits transcription and DNA replication by inhibiting topoisomerase II Bleomycin fragments formed DNA chains. Route of Administration I.V, doxorubicin given intravesically for bladder cancer Clinical uses: Dactinomycin for paediatric cancers Doxorubicin for acute leukaemias, lymphomas, and solid tumours Bleomycin for lymphomas and certain solid tumours Adverse effects Doxorubicin induces dose-dependent cardiotoxicity, due to irreversible free radical damage to the myocardium. Bleomycin may cause pulmonary fibrosis Mitotic inhibitors Vinca alkaloids-vincristine, vinblastine, vinorelbine and etoposide Mechanism Binding of tubulin and inhibiting polymerization of microtubules, which are necessary to form the mitotic spindle This prevents mitosis and arrests dividing cells at metaphase Route of admn. Vinca alkaloids are given by i.v and etoposide by oral or i.v Indications For acute leukaemias, lymphomas and some solid tumours Adverse effects: tubulin polymerization is indiscriminate, therefore they inhibit processes involving microtubules and cell division.  TOPOISOMERASE INHIBITORS There are two types of topoisomerase, known as topoisomerase I and topoisomerase II. Topoisomerase I makes single-strand cuts, and topoisomerase II makes double-strand cuts. Of the four topoisomerase inhibitors in current use, two—topotecan and irinotecan—inhibit topoisomerase I, and the other two—etoposide and teniposide—inhibit topoisomerase II. The actions of these drugs are partly like those of the antitumor antibiotics, discussed previously, which inhibit topoisomerase II and intercalate DNA.  Topotecan Mechanism of Action Topotecan [Hycamtin], an inhibitor of topoisomerase I, binds to the DNA– topoisomerase I complex. The drug does not prevent topoisomerase I from making a single-strand cut in DNA, but does prevent the enzyme from resealing the cut. As a result, there is an accumulation of DNA with multiple single-strand cuts. Of note, these single-strand cuts, by themselves, are not harmful: If the drug is removed, the cuts can be repaired. However, if the cell attempts to replicate DNA while the drug is still present, irreversible double-strand breaks will be produced, thereby causing cell death. Because ongoing replication of DNA is needed for cell death, topotecan is most active in S phase.  Therapeutic Uses Topotecan is approved for metastatic cancer of the ovary. It is also approved for cervical cancer that returns after previous treatment or that is resistant to treatment. Finally, it is approved for relapsed or refractory small cell lung cancer Etoposide Etoposide [Toposar], a drug derived from podophyllotoxin (a naturally occurring plant alkaloid), inhibits topoisomerase II. Etoposide does not prevent topoisomerase II from making double-strand breaks in DNA, but it does prevent the enzyme from resealing those breaks. Cell death results from accumulation of DNA with multiple breaks. Cells in S and G2 phases are most sensitive. Etoposide is approved only for refractory testicular cancer and small cell cancer of the lung, but is used off-label against many other tumors  Miscellaneous anti-cancer agents Name Mechanism Route Indications Adverse Notes effects Methylhydrazine Generalized - actions with MAO 1 line for cytotoxicity, oral st Procarbazine actions and lymphoma and adverse reaction cytotoxicity.Inhibits Hodgkin’s in combination DNA & RNA with alcohol synthesis Inhibition of oral Chronic myeloid Generalized Hydroxyurea ribonucleotide & leukaemis cytotoxicity, deoxyribonucleotides (CML) Inhibits synthesis of Acute Hepatotoxicity, Monitoring of asparagine in tumour lymphoblastoid and pancreatic organ fuction Crisantaspase cells, a bacterial i.m, s.c leukaemia toxicity, CNS essential in asparaginase (ALL) depression, crisantaspase anaphylaxis therapy Related to DDT, adrenosuppression interferes with Mitotane formation of adrenal Tumours of the steroids, selective cytotoxic effect on oral adrenal cortex the cells of the adrenal cortex Like doxorubicin, Amsacrine intercalates base pairs Acute myeloid Bone marrow Electrolyte in DNA double helix, i.v leukaemia suppression, monitoring no formation of RNA (AML) cardiotoxicity due required to hypokalaemia Endocrine therapy The growth of some cancers are hormone dependent. Development of such tumours can be inhibited by surgical removal of the source of the driving hormone. The source may be the: Gonads Adrenals Pituitary Use of hormones and anti-hormones preferred. Side effects of endocrine therapy depends on the physiological role of the hormone being antagonized. The hormones used include: Adrenocortical steroids eg. Prednisolone They inhibit the growth of cancers of the lymphoid tissues and blood Also used to treat some of the complications of the cancer eg. Oedema Oestrogen antagonists e.g.tamoxifen These are competitive inhibitors at oestrogen receptors Inhibition of the stimulatory effects of oestrogen suppresses the division and mutiplication of breast cancer cells Tamoxifen is indicated for use in pre-menopausal women with metastatic disease-shown to increase survival times Oestrogens eg. Diethylstilboestrol Have antiandrogenic effects and can be used to suppress androgen-dependent prostatic cancer Progesterones Inhibit endometrial cancer and carcinomas of the prostate and breast. Androgen antagonists eg. Flutamide Inhibit androgen dependent protatic cancers Gonadotrophin releasing hormone (GnRH) analogues have similar effect as they inhibit GnRH release via a negative feedback mechanism. Immunotherapy A recent advance derived from the observation that bacterial infections sometimes leads to regression tumours (indirect immunostimulation) Approaches of immunotherapy: Tumour specific monoclonal antibodies to target drugs specifically to cancerous cells (magic-bullet) The use of vaccines eg. BCG to provide non-specific immunostimulation The use of specific vaccines prepared using tumour cells from similar cancers, in order to raise an adaptive immune response against the cancer Immunostimulation using drugs eg. Levamisole The use of cytokines to regulate the immune system to target the cancer eg.interferon-, interlukin-2. The use of recombinant colony stimulating factors to reduce the level and duration of neutropenia following cytotoxic therapy eg. Recombinant human colony stimulating factor. Treatment schedules in cancer chemotherapy Combination therapy is adopted to: Increase the cytotoxicity Reducing general toxicity Decreases the possibility of resistance Example: methotrexate (myelosuppression) + vincristine (neurotoxicity) Drugs with low myelotoxicity (cisplatin, bleomycin) are good for combination regimes Drugs are usually given in large doses intermittently. In several courses wi between courses. This approach has the advantage of: Allowing the bone marrow to regenerate during the intervals Effectiveness, as the same total dose of an agent is more effective when given in one or two large doses than in multiple small doses Drug Resistance in chemotherapy Resistance to neoplastic drugs may be: Primary (present when the drug is given initially) Aquired (developing during treatment) Due to adaptation of the tumour cells Mutation leading to the emergence of less affected or unaffected cells. Mechanisms of resistance Increased efflux of drug from cancer cells (MDR) due increased expression of p-glycoprotein (transport protein) P-glycoprotein-thought to protect cells against toxins Verapamil inhibits this transport system Decrease in the amount of drug taken up by the cancer cell (methotrexate) Insufficient activation of the drug eg. Mercaptopurine, fluorouracil Increase in inactivation (cytarabine, mercaptopurine) Increased concentration of target enzyme (methotrexate) Decreased requirement for substrate (crisantaspase) Increased utilization of alternative pathways  rapid repair of drug-induced lesion (alkylating agents) Altered activity of target eg. Modified topoisomerase II (doxorubicin) Drawbacks in cancer chemotherapy Severe toxic effects of many agents, particularly bone marrow suppression and nausea and vomiting (cisplatin) Metoclopramide (I.v) very useful for chemotherapy induced nausea and vomiting, often in combined therapy with Dexamethasone, lorazepam. Extrapyramidal symptoms of metoclopramide (young adults & children) reduced by diphenhydramine 5-HT3 antagonists eg. Ondansetron used to control nausea and vomiting Myelosuppression: Removing some of the patients bone marrow before and replacing after chemotherapy. Use of colony stimulating factors. The lack of selectivity of drugs against tumour cells Use of monoclonal antibodies to target the tumour cells Impossibility of eliminating the total malignant cell population with therapeutic doses and the inadequacy of the host’s immune response to deal with the remaining cells Use of biological response modifiers eg. Interferon and interlukin