ANTICANCER DRUGS

By Dr. Harrison R. Chuwa, MD M.Med Clinical Oncologist Ocean Road Cancer Institute

 Cancer is a disease of cells characterised by a shift

in the control mechanisms that govern cell proliferation and differentiation. Neoplastic cells usually express cell surface antigens that may: be of foetal type, display other signs of apparent immaturity, exhibit qualitative or quantitative chromosomal abnormalities. Such cells proliferate excessively and form local tumours that can compress or invade adjacent normal structures.

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 A small subpopulation of cells, tumour stem cells

retain the ability to undergo repeated cycles of proliferation as well as to migrate to distant sites in the body to colonise various organs in the process called metastases. Treatment regimens: Presently about one third of patients are cured with local modalities (surgery/or radiation therapy). This modality is quite effective when the tumour has not metastasized at the time of therapy

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 At present about 50% of the patients with cancer can

be cured with chemotherapy contributing 10 15% of the patients. Cancer chemotherapy as currently employed can be curative in certain disseminated neoplasms that have undergone either gross or microscopic spread by the time of diagnosis (testicular cancer, non-Hodgkins lymphoma, Hodgkins disease, choriocarcinoma as well as childhood cancers such as acute lymphoblastic leukaemia,Burkitts lymphoma Wilms tumour and embryonal rhabdomyosarcoma).

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 Ideal anticancer drugs should eradicate cancer cells

without harming normal tissues. Unfortunately no currently available agents meet this criterion. Clinical use of these drugs involves weighing benefits against toxicity. Cell cycle: All cells normal and neoplastic traverse through phases before and during cell division.

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 G0 phase: A varying time in a quiescent phase outside the

cycle. G1 phase (40% of the time): The cell is preparing for S phase synthesising messenger RNAs (mRNA) and proteins needed for DNA replication. S phase ( 39% of the time): DNA synthesis and replication of genome.

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 G2 phase (19% of the time): The cell now has double the number of

chromosomes. Must duplicate all other components for allocation to the two daughter cells. Synthesis of the necessary mRNAs and proteins occurs. M phase (Mitosis 2% of the time): Mitosis is divided into four stages

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 Prophase: The duplicated chromosomes condense, each now

consisting of two daughter chromatids (the original chromosome and a copy). These are released into the cytoplasm as the nuclear membrane disintegrates. Meta phase: The chromosomes are aligned at the equator.

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 Anaphase: The mitotic apparatus captures the chromosomes

and draws them to the opposite poles of the dividing cell. Telophase: A nuclear membrane forms round each set of chromosomes. Finally the cytoplasm divides between the two forming daughter cells.

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 Cell cycle specific (CCS) drugs:

Antimetabolites: Capecitabine, cladribine, cytarabine, fludarabine,

mercaptopurine, methotrexate and thioguanine. Antibiotics: Bleomycin. Epipodophyllotoxins: Etoposide, teniposide. Taxanes: Docetaxel, paclitaxel.

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 Vinca alkaloids: Vinblastin, vincristine and vinorelbine. Cell cycle non-specific (CCNS) drugs: Alkylating agents: Busulfan, carmustine, cyclophosphamide lomustine

mechlorethamine, melphalan and thiotepa. Anthracyclines: Daunorobicin, doxorubicin, epirubicin and idarubicin and mitoxantrone.

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 Antitumour antibiotics: Dactinomycin, mitomycin. Camptothecins: Irinotecan and topotecan. Platinum analogues: Carboplatin, cisplatin and oxaliplatin.

General toxic effects of anticancer drugs:

The main effect of anticancer drugs is on cell division.

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 Anticancer drugs will affect all rapidly dividing normal

cells and thus they are likely to produce, to a greater or less extent the following toxic effects: (i) Myelosuppression with decreased leukocyte production and thus decreased resistance to infection.(ii) Impaired wound healing. (iii) Damage to gastrointestinal epithelium. (iv) Loss of hair (alopecia). (v) Depression of growth in children.(vi) Sterility.(vii) Teratogenicity.

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 (A) Alkylating agents:

1.Bis(chloroethyl)amines: Cyclophosphamide, mechlorethamine, chlorambucil

and melphalan. 2. Nitrosoureas: BCNU (Carmustine), CCNU (Lomustine), MethylCCNU (Semustine). 3. Aziridines: Thiotepa, Triethylenemelamine. 4. Alkylsulfonate: Busulfan.

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 Mechanism of action:
Alkylating agents exert cytotoxic effects via transfer

of their alkyl groups to various cellular constituents. Alkylation of DNA within the nucleus probably represents the major interaction that leads to cell death. The drugs react with other groups (sulfhydryl, amino, hydroxyl, carboxyl and phosphate) of cellular nucleophiles as well.

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 The major site of alkylation within DNA is the N7

position of guanine but other bases are also alkylated to lesser degrees (N1.N3 of cytosine, and O6 of guanine). Drug resistance: d capability to repair DNA lesions. d permeability of the cell to the drug. d production of glutathione which which inactivates the drug through conjugation or through d glutathione S-transferase activity which catalyses the conjugation.

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 Pharmacological effects:

Alkylating agents have vesicant effects and can

damage tissues at the site of injection as well as produce systemic toxicity (bone marrow,Git and the reproductive system). Emetogenic effects are mediated by the cns and can be reduced by pretreatment with 5-HT3receptor antagonist (ondansetrone or granisetron. SC inj. of mechlorethamine or carmustine leads to tissue necrosis and sloughing.

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 Cyclophosphamide, a nitrogen mustard, is a pro-drug

which is converted by theMFO system to 4hydroxycyclophosphamide which is in equilibrium with aldophophamide. These two active metabolites are delivered by the blood stream to both tumour and normal tissue where nonenzymatic cleavage of aldophosphamide yields the cytotoxic formsphosphoramide mustard and acrolein. Acrolein may damage the urinary bladder and cause haematuria.

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 The liver is protected by enzymatic formation of

inactive metabolites (4-ketocyclophosphamide and carboxyphosphamide). Cyclophosphamide, melphalan, chlorambucil, busulfan and more recently temozolomide are given more commonly by the oral route. Busulfan has specificity for the granulocyte series and is therefore of particular value in therapy of chronic myelogenous leukaemia.

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 2. Nitrosoureas (carmustine, lomustine, metyl-CCNU

ie semustine): These require biotransformation which occurs by nonenzymatic decomposition to metabolites with both alkylating and carbomoylating activities. They are lipid soluble hence useful in treating brain tumours. Initial T is about 6hrs later T is about 1- 2 days. Streptozocin, a sugar containing nitrosourea, has minimal bone marrow toxicity used in therapy of insulin secreting islet cell ca. of the pancrease.

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 3. Drugs probably acting as alkylating agents

(procarbazine, dacarbazine, altretamine[hexamethylmelamine], cisplatin and carboplatin): (i) Procarbazine: This is a methylhydrazine derivative and is orally active. Mechanism of action: Uncertain but has been found to inhibit the synthesis of DNA, RNA and protein

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 Oxidative metabolism of this drug by microsomal

enzymes generates azoprocarbazine and H2 O2 which may be responsible for DNA strand scision. One of the metabolites is a weak MAO inhibitor. Clinical uses: Used in combination (MOPP) regimens for Hodgkins disease, non-Hodgkins lymphoma and brain tumours. Adverse effects: Leukaemogenic teratogenic and mutagenic.

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 (ii) Dacarbazine:

A pro-drug,activated in the liver and the product is

cleaved in the target cell to release an alkylating derivative. Advers effects: Myelotoxicity and severe nausea and vomiting. (iii) Cisplatin: A water soluble planar coodination complex containing a central platinum atom surrounded by two chlorine atoms and two ammonia groups.

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 Mechanism of action:

Inside the cell Cl- dissociates leaving a reactive

complex that reacts with water and then interacts with DNA. It causes strand cross-linking probably between N7 and O6 of adjacent guanine molecules which results in local denaturation of the DNA chain. Cisplatin is given by slow iv injection or infusion.

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 Adverse effects:

It is seriously nephrotoxic unless regimens of

hydration and diuresis are instituted. Has low myelotoxicity, causes severe nausea and vomiting. The 5-HT3receptor antagonist,ondansetron is very effective in preventing nausea and vomiting and has transformed cancer chemotherapy with cisplatin. (iv) Carboplatin (2nd generation platinum analog)

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 Carboplatin is a derivative of cisplatin and is less

nephrotoxic,neurotoxic,ototoxic and less severe nausea and vomiting than cisplatin but is more myelotoxic. Carboplatin is now being more used in place of cisplatin in combination therapy. Oxaliplatin (3rd generation platinum analog) has similar mechanism of action to cisplatin. Widely used for colorectal cancer. Peripheral sensory neuropathy often triggered or worsened upon exposure to cold is dose limiting.

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 (vi) Altretamine (hexamethylmelamine):

Structurally similar to triethylenemelamine.

It is relatively insoluble and is available only in the

oral form. It is demethylated in the liver to the pentamethylmelamine and tetramethylmelamine metabolites. Used in ovarian cancer patients. Adverse effects: Nausea,vomiting,myelosuppression,somnolence,moo d changes and peripheral neuropathy have been reported.

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 Clinical uses of alkylating agents:

They are used in the treatment of a wide variety of

haematologic and solid cancers. (B) Antimetabolites: (i) Folate antagonists (methotrexate): Folates are actively taken up into cells where they are converted to polyglutamates. In order to act as coenzymes,folates must be reduced to tetrahydrofolate (FH4). This reaction is catalysed by DHF reductase.

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 Methotrexate has higher affinity for DHF reductase

than DHF. Methotrexate thus inhibits the enzyme and depletes intracellular THF. Pharmacokinetics: Methotrexate can be given orally,iv,im and intrathecally. It has low lipid solubility and thus does not cross the BBB. It is actively taken up into cells by the transport system used by folate and is metabolised to polyglutamate derivatives.

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 Adverse effects:

Depression of bone marrow, damage to the

epithelium of the Git, pneumonitis can occur and nephrooxicity. High doses should be followed by rescue with folinic acid ( a form of THF). (ii) Pyrimidine analogues: (a) Fluorouracil an analogue of uracil is converted into a fraudulent nucleotide fluorodeoxyuridine monophosphate (FDUMP)

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 The fraudulent nucleotide interacts with

thymidylate synthetase but cannot be converted into DTMP (thymidylate). The result is inhibition of DNA synthesis but not RNA or protein synthesis. Fluorouracil is usually given parenterally. Adverse effects: Git epithelial damage. Myelotoxicity,cerebellar disturbances. (b) Cytarabine (cytosine arabinocide) enters the target cell and undergoes the same phosphorylation reactions as the physiological nucleoside to give the cytosine arabinoside triphosphate which inhibits DNA polymerase.
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 Adverse effects: Nausea,vomiting and has adverse effects on bone

marrow and Git. (c) Gematabine a promising new analogue of cytarabine. Has fewer side effects:- an influenza like syndrome and mild myelotoxicity. (iii) Purine analogues (fludarabine, pentostatin,cladribine, mercaptopurine and tioguanine):

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 (a) Fludarbine is metabolised to triphosphate and

inhibits DNA synthesis by actions similar to cytarabine. It is myelosuppressive. (b) Pentostatin has a different mechanism. It inhibits adenosine deaminase, the enzyme that catalyses deamination of adenosine to insine. This action interferes with critical pathways in purine metabolism and can have significant effects on cell proliferation.

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 (C) Cytotoxic antibiotics:

(a) Anthracyclines (dxorubicin,daunorubicin,

epirubicin,aclarubicin ann mitoxanthrone[mitozantrone]) (i)Doxorubicin and daunorubicin: Daunorubicin was the first agent in this class and is still used in treatment of acute myeloid leukaemia. Doxorubicin has a broad spectrum of clinical activity (haematological and a wide range of solid malignanccies).

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 Mechanism of action:

Main cytotoxic action is mediated through an effect

on topoisomerase II (a DNA gyrase) the activity of which is markedly increased in proliferating cells. During replication of DNA helix reversible swivelling needs to take place around the replication fork in order to prevent the daughter DNA molecule becoming inextricably entangled during mitotic segregation

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 The swivel is produced by topoisomerase II which

nicks both DNA strands and subsequently reseals the breaks. Doxorubicin intercalates in the DNA and its effect is in essence to stabilise the DNA topoisomerase II complex after the strands have been nicked, thus causing the process to seize up at this point. Anthracyclines also bind to cellular membranes to alter fluidity and ion transport and also generate semiquinone free radicals and O2 radicals( the cause of the drugs cardiac toxicity).

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 (b) Dactinomycin:

An antitumour antibiotic isolated from streptomyces

organisms. Mechanism of action: Dactinomycin intercalates in the minor groove of DNA between adjacent guanosine-cytosine pairs interfering with the movement of RNA polymerase along the gene thus preventing transcriptions. It also acts like anthracyclines on topoisomerase II.

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 Clinical uses: Dactinomycin is used to treat paediatric tumours such

as Wilms tumour, rhabdomyosarcoma and Ewings sarcoma. It also has activity against gestational trophoblastic disease. (c) Bleomycins: A group of metal chelating glycopeptide antibiotics that degrade preformed DNA, causing fragmentation and relaese of free bases.

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 Their action on DNA is thought to involve chelation of

ferrous iron and interaction with oxygen resulting in the oxidation of the iron and generation of superoxide and/or hydroxyl radical. Bleomycin is most effective in G2 phase of the cell cycle and mitosis. Adverse effects: It causes little myelosuppression. Pulmonary fibrosis (10% and is fatal in 1%) Mucocutaneous reactions(palms often affected), and hyperpyrexia.

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 (d) Mitomycin: Mitomycin C is an antibiotic isolated from

Streptomyces caespitosis. It undergoes enzymatic activation in the cells and function as a bifunctional alkylating agent. Alkylating at O6 of guanine. It cross-links DNA and may also degrade DNA through the generation of free radicals. It causes marked myelosuppression and can also cause kidney damage and fibrosis of lung tissue.

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 (e) Procarbazine (refer to notes on alkylating agents). (f) Hydroxycarbamide (Hydroxyurea): A urea analogue that inhibits ribonucleotide

reductase, thus interfering with conversion of ribonucleotides to deoxyribonucleotides. Adverse effects: Bone marrow depression. General adverse effects common to all anticancer drugs.

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 (D) Plant Derivatives: (i) Vinca alkaloids (vincristine, vinblastine, vindestine

and vinorelbin): Mechanism of action: They act by binding to tubulin and inhibiting its polymerisation into microtubules, thus preventing spindle formation in mitosing cells and causes arrest at metaphase. Their effects only become manifest during mitosis.
They also inhibit leukocyte phagocytosis and

chemotaxis and axonal transport in neurons- all these activities involve microtubules.

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 Adverse effects: Relatively non toxic. Vincristine has mild myelosuppressive activity but

causes paraethesia (sensory changes and muscle weakness). Vinblastine is less neurotoxic but causes leukopaenia. Vindestine has moderate myelotoxicity and neurotoxicity.

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 (ii) Taxanes: Paclitaxel and docelatel. These act on microtubules stabilising them (in effect

freezing them) in the polymerised state. The effects are similar to those caused by vinca alkaloids. Paclitaxel is given by iv infusion. Docelatel by mouth. Both used in treatment of breast cancer. Paclitaxel is given with carboplatin in treament of ovarian cancer.

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 Adverse effects:

Bone marrow suppression, cumulative neurotoxicity.

Resistant fluid retention (particularly oedema of legs)

can occur with docelatel. Hypersensitivity to both compounds is likely to occur and requires pretreatment with corticosteroids and antihistamines.
(iii) Etoposide:

Derived from mandrake root.

Inhibits mitochondrial function and nucleoside

transport and has an effect on DNA gyrase.

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 Adverse effects: Nausea, vomiting, myelosuppression and hair loss. (iv) Campothecins: Irinotecan and topotecan.

Bind to and inhibit topoisomerase I found in high

concentrations throughout the cell cycle. Adverse effects: Have fewer adverse effects than most other anticancer drugs-diarrhoea and reversible bone marrow depression.

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 (E) Hormones:
(i) Glucocorticoids: Inhibit lymphocyte proliferation (leukaemias and

lymphomas). Have a supportive in other cancers on the basis of their effects on raised intracranial pressure. (ii) Oestrogens: Fosfestrol, activated by acid phosphatase in prostatic tissue to yield stilboestrol, blocks the effect of androgens in androgen dependent tumours.

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 Prostatic tumours are best treated with

gonadotrophin releasing hormone analogues. Oestrogens can be used to recruit resting mammary cancer cells into the proliferating pool of cells thus allowing a greater killing efficacy of the cytotoxic drugs that are given. (iv) Progestogens: Megestrol and medroxyprogesterone are useful in endometrial neoplasms and in renal tumours with steroid receptors.

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 (v) Gonadotrophin releasing hormone analogues: Goserelin an analogue of gonadotrophin releasing

hormone can under certain circumstances inhibit gonadotrophin release. Used in advanced breast cancer in premenopausal women and prostate cancer. The surge of testosterone in patients treated this way can be prevented by antiandrogens eg cyproterone.

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 Octreotide an analogue of somatostatin is used to

treat various hormone-secreting tumours of the git eg VIPomas, glucagonomas, carcinoid syndrome and gastrinomas. These tumours have somatostatin receptors, activation of which inhibits proliferation and hormone secretion. (vi) Hormone antagonists:
(a) Antioestrogens: Tamoxifen competes with

endogenous oestrogens for oestrogen receptors and inhibits transcription of oestrogen responsive genes. Tamoxifen is also cardioprotective.

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 (b) Antiandrogens: Androgen antagonists Flutamide and Cyproterone

are used in prostate tumours. (c) Adrenal hormone synthesis inhibitors: Have effects on postmenopausal breast cancer. Formestane acts at a late stage it inhibits the enzyme aromatase which metabolises androgens to oestrogens. Trilostane and Aminoglutethimide which inhibit sex hormone synthesis at an early stage.Replacement of corticosteroids is necessary with these latter two.

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 (F) Radioactive isotopes: Radioactive iodine (131I) is used in treatment of

thyroid tumours. (G) Miscellaneous agents: (i) Crisantaspase: A preparation of the enzyme asparaginase given im or iv. It breaks down asparagine to aspartic acid and ammonia. It is active against tumour cells that have lost the capacity to synthesise asparagine.

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 Such tumour cells now require exogenous

asparagine (acute lymphoblastic leukaemias). Most normal body cells are able to synthesise asparagine. Adverse effects: Nausea, vomiting cns depression, anaphylactic reactions and liver damage. The drug has little suppressive effect on the bone marrow,git mucosa or hair follicles.

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 (ii) Mitotane: Has cytotoxic action on cells in the adrenal cortex.It

is used for tumours of these cells. (iii) Amsacrine: Has mechanism of action similar to that of doxorubicin. Bone marrow depression and cardiotoxicity have been reported. (iv) Monoclonal antibodies: Immunoglobulins produced by cell culture selected to react with antigens specifically expressed on cancer cells.

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 The immunoglobulins attach to specific antigen with

the Fab portions of the molecule leaving the Fc portion jutting out. This activates the hosts immune mechanisms and the cancer cell is killed by complement mediated lysis or attack by the killer cells. Some monoclonal antibodies attach and inactivate growth factor receptors on cancer cells thus inhibiting the survival pathway and promoting apoptosis.

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 (a) Rituximab: A monoclonal antibody that attaches to CD20 protein

on B cells and kills by complement-mediated lysis or by inducing apoptosis. It sensitises resistant cells to chemotherapeutic drugs. It is used for B-cell lymphomas being effective in 4050% of cases when combined with standard chemotherapy.
Adverse effects: Hypotension,chills & fever during

initial infusions.Subsequently hypersensitivity reactions. A cytokine-release reaction can occur and may be fatal. May worsen cardiovascular disorders.

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 (b) Trastuzumab: This is a humanised murine monoclonal antibody that

binds to a protein termed Her2/neu which is a member of the epidermal growth factor receptor family receptors with integral tyrosine kinase activity. In addition to inducing host immune response trastuzumab induces cell cycle inhibitors p21 and p27. In about 25% of breast cancer pts, the tumour cells over express this receptor and the cancer proliferates rapidly.

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 Early results show that trastuzumab given with std

chemotherapy has resulted in a 79% 1 year survival rate in treatment nave pts with this aggressive form of breast cancer. Adverse effects: Similar to those with rituximab. (v) Imatinib mesylate (aka Gleevec,Glivec) A molecule inhibitor of signalling pathway kinases. It inhibits platelet derived growth factors ( a receptor tyrosine kinase).

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 Imatinib mesylate inhibits other asoects of signal

transduction, specifically cytoplasmic kinase considered to be a unique factor in pathogenesis of chronic myeloid leukaemia. It has been licensed for the treatment of this tumour. (vi) Biological response modifiers: These agents enhance the hosts response to tumours.

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 Biological response modifiers include ( interferon

,aldesleukin which is a preparation of interleukin2 and tretinoin). The agents are used for selected tumours. Tretinoin is a powerful inducer of differentiation in leukaemic cells and is used as adjunct to chemotherapy. Resistance to Anticancer Drugs: Mechanisms include:(a) Insufficient activation of the drug (mercaptopurine,fluorouracil & cytarabine).

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 (b) Decreased accumulation of cytotoxic drugs in

cells as a result of the increased expression of cell surface energy-dependent drug transport proteins (doxorubicin,vinblastine, dactinomycin etc) (c) Decrease in the amount of drug taken up by the cell (methotrexate). (d) Increase in inactivation (cytarabine, mercaptopurine). (e) Increased concentration of target enzyme (methotrexate). (f) Decreased requirement of substrate (crisantaspase).

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 (h) Increased utilisation of alternative metabolic

pathways (antimetabolites). (i) Rapid repair of drug induced lesions (alkylating agents). (j) Altered activity of target for example modified topoisomeraseII (doxorubicin). (k) Mutation in the p53 gene and over expression of the bcl-2 gene family (several cytotoxic drugs).

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