ANTI CANCER DRUGS

INTRODUCTION Definition: Cancer is a disease characterized by uncontrolled multiplication and spread of abnormal forms of the body's own cells. The terms cancer, malignant neoplasm (neoplasm simply means 'new growth') and malignant tumor are synonymous. TWO TYPES OF TUMOUR 1 BENIGN TUMOUR 2 MALIGNANT TUMOUR 7

THE PATHOGENESIS OF CANCER. Cancer cells manifest four characteristics that distinguish them from normal cells uncontrolled proliferation dedifferentiation and loss of function invasiveness Metastasis

General principles for cancer therapy The cells of a solid tumour can be divided into 3 compartments: Compartment A Continuously dividing cells Compartment B Resting cells in G0 phase Have an ability to enter the cell cycle Compartment C No ability to divide

Only the cells in the compartment A i. e Only the cells in the compartment A i.e. the dividing cells are susceptible to the main currently available cytotoxic drugs. But these cells are only 5% of the entire tumour. The cells in the compartment B tend to pose a problem as they are not susceptible to cancer chemotherapy but are likely to enter the compartment A following the course of chemotherapy. Most of the currently available anti cancer drugs are antiproliferative. They have no specific inhibitory effect on invasiveness, the loss of differentiation or the tendency to metastatise. Their main action is on S phase of the cell cycle and hence results into the DNA damage causing apoptosis.

Lastly , the cancer chemotherapy also acts on the normal tissues and thereby they produce a some general toxic effects like : bone marrow suppression (myelosuppression) resulting in decreased leucocyte production and hence increased resistance to infection. Impaired wound healing Loss of hair Damage to the gastrointestinal epithelium Growth retardation in children Sterility Teratogenecity They can themselves be carcinogenic Kidney damage due to excess urate deposition in the tubules ( due to extensive purine catabolism) Severe nausea and vomitting ( reduced patient compliance)

Drugs used in cancer chemotherapy Cytotoxic Drugs Alkylating agents Antimetabolites Antimitotics Cytotoxic antibiotics Plant derivatives Hormones Miscellaneous agents

Alkylating agents The nitrogen at position 7 (N7) of guanine is strongly nucleophilic and is the main target for the alkylating agents. N1 and N3 of adenine and N3 of cytosine may also be affected. Most of these agents are bifunctional i.e. they have two alkylating groups and can cause inter as well as intrachain cross-linking. This can not only interfere with transcription but also replication .

Other effects of alkylation at guanine N7 are excision of the guanine base with main chain scission, or pairing of the alkylated guanine with thiamine instead of cytosine and eventually substitution of the GC pair by an AT pair. The effects of this alkylation are manifested during S phase, resulting in block at G2 phase and subsequent apoptotic cell death. Side effects: bone marrow depression, git disturbances at very high doses. neurotoxicity With prolonged use it can lead to sterility

Intrastrand and interstrand crosslinking in DNA

Types of alkylating agents are: 1. Nitrogen Mustards Cyclophosphamide Ifosphamide Chlorambucil Melphalan Mecholrethamine Bendamustine Glufosfamide 3. Agents with trizene group Dacarbazine Procarbazine Timozolamide 4. Ethelenamines Thiotepa Hexamethylmelamine 5. Agents with sulfate group Busulfan Platinum compounds: Cisplatin, carboplatin 2. Nitrosoureas Lomustine Carmustine Semustine Streptozocine

Cyclophosphamide/ifosfamide are prodrugs Metabolized to aldophosphamide Tissues Acrolein Phosphoramide mustard causes hemorrhagic cystitis Alkyl group which causes N7 guanine and causes inhibition of DNA Hepatic cytochrome oxidase Treatment: Intake of fluids and –SH group donors like Mesna

Other imp points of alkylating agents: Streptozocine: destroys the beta cells of pancreas so approved for treatment of insulinoma. Also used to induce diabetes mellitus in experimental animals. Busulfan: Selective action on bone marrow, depressing the formation of granulocytes and platelets in low dose and red blood cells in high dose. Use: chronic granulocytic leukemia, as a preparative for bone marrow transplantation Main side effect is pulmonary fibrosis and neurotoxicity (seizures) Also can cause adrenal suppression Estramustine: Estrogen + mechlorethamine Approved for the treatment of prostatic carcinoma S/E – Gynaecomastia, loss of libido, thromboembolism

Cisplatin: M/A: it has a platinum atom surrounded by two chloride atoms and two ammonia groups. When it enters the cell the cl- group dissociates leaving the reactive complex to interact with DNA. It causes intrastrand crosslinking between N7 and O6 of adjacent guanine molecules leading to denaturation of DNA. Side effects: nephrotoxicity,(hydration and diuresis required) Severe nausea and vomiting (ondansetron given) Tinnitus and hearing loss Low myelotoxicity Others: peripheral neuropathies, huperuricaemia, anaphylactic reactions. Use: solid tumours of testes and ovary Carboplatin: derivative of cisplatin More myelotoxicity Less neurotoxocity, nephrotoxicity , ototoxicity, nausea and vomiting. Cisplatin – max S/E and min potency Carboplatin – intermediate Oxaliplatin – min S/E and max potency

Antimetabolites These drugs act in the s-phase of the cell cycle so only dividing cells are responsive Folic acid analogues Purine analogues Pyrimidine analogues Methotrexate 6-mercaptopurine 5-flourouracil Pemetrexed 6-thioguanine Capecitabine cladrabine Gemcitabine Pentostatin Cytarabine Fludrabine Methotrexate: Inhibitor of dihydrofolate reductase enzyme which is required for synthesis of thymidylate and hence DNA formation. At high dose – by diffusion enters the normal cells and inhibits DNA formation in the normal cells

S/E: BM suppression, diarrhoea, mucositis due to inhibition of rapidly proliferating cells Drug of choice for overdose: Folinic acid or leucovorin or citovorum factor. It directly gets converted to tetrahydrofolate bypassing the requirement of dihydrofolate reductase. On the surface of cancer cells, there is an influx pump which takes in methotrexate at low dose. Inside the cells it binds with polyglutamine Forms methotrexate polyglutamine complex which serves as reservoir of methotrexate leading to long lasting effect. MTX has affinity for cells having high chromosome no. like placental, fetal and germ cells so it is drug of choice for choriocarcinoma in which single drug treatment is used.

Eliminated by kidney- tubular secretion by acidic pumps. NSAIDS can saturate these pumps leading to decreased secretion of MTX causing toxicity. Uses: Almost all types of cancers, Burkitt’s lymphoma, choriocarcinoma, breast carcinoma, osteosarcoma. It also has immunosuppressive property so it is used for organ transplant, RA, IBD, Psoriasis, Ectopic pregnancy. Resistance: - mutation of influx pumps - induction of efflux pumps - mutation of DHFRase enzyme Pemetrexed: inhibitor of thymidine synthase. Folic acid or vit B12 can reduce the toxicity of pemetrexed Approved for tumour of mesothelioma S/E- peripheral neuropathy in hand and foot region called as hand-foot syndrome.

Mechanism of action methotrexate and fluorouracil

Pyrimidine analogues: 5-FU is the prodrug Active metabolite is 5- fluorodeoxyuridine monophosphate Cells are unable to differentiate between 5F-dUMP and dUMP 5F-dUMP CH3 thymidine synthase Fluorothymidine Inhibits DNA synthesis because of incorporation of modified neucleotide Leucovorin given with 5FU increases formation of fluorothymidine causing increased effect of 5FU. This concept is used in colorectal cancer. FOLFOX regimen of colorectal cancer. FOL- Folinic acid FOLFIRI F- 5FU, OX- oxaliplatin, IRI- irinotecan

Metabolized at the level of lung tissue by endothelial enzymes. Given by i.v route Alternative: capecitabine which is prodrug of 5FU given by oral route. Gemcitabine/Cytarabine: Act as prodrugs. Combines with 3PO4 groups and converts to Gemcitabine triphosphate modified nucleotides which with Cytarabine triphosphate the help of DNA polymerase gets incorporated into DNA inhibiting DNA synthesis Gemcitabine use: non beta cells cancer of pancreas S/E: flu like symptoms

6-methylmercaptopurine HGPRTase Purine structure DNA polymerase Purine analogue: 6-MP ( prodrug) 6-methylmercaptopurine HGPRTase Purine structure DNA polymerase Incorporation in DNA. So inhibition of DNA synthesis. Metabolized by xanthine oxidase to form uric acid. Some part is metabolized by methyl transferase enzyme. 6-Tiagabine: acts in the same way as 6-MP but metabolized only by methyl transferase enzyme. Azathioprine: prodrug of 6-MP. Used only as immunosuppressive.

Pentostatin: inhibitor of adenosine deaminase. Used in hairy Pentostatin: inhibitor of adenosine deaminase. Used in hairy cell leukemia. Cladribine: used in hairy cell leukemia Antimitotics Vinka alkaloids Texans Ixebepilone Vinka alkaloids: vincristine, vinblastine, vinorelbine MOA: inhibition of spindle formation S/E: - SIADH - Bone marrow suppression - Peripheral neuropathy.

Taxanes: Paclitaxel, docitexal, cabazitexal MOA: inhibition of spindle formation Approved for the treatment of breast carcinoma Paclitaxel + carboplatin: treatment of choice in ovarian cancer. S/E: Hypersensitivity reaction and to inhibit it paclitexal is combined with albumin to form abpaclitaxel bone marrow suppression peripheral neuropathy Ixebepilone: MOA same as texans but more potent than paclitexal so used in treatment of paclitexal resistant breast cancer Advantage – no hypersensitivity reaction

Anti tumour antibiotics Anthracycline antibiotics Mitoxantrone Mitomycin c Bleomycin Actinomycin D Most imp mechanism of action – Free radicle formation S/E: Cardiotoxicity – cardiomyopathy after 2-3 months. Treatment– dexrazoxane, alpha – tocoferol – they are free radicle scavengers Bone marrow suppression

ANTHRACYCLINES: Doxorubicin,Idarubicin, epirubicin, aclarubicin, mitoxantrone. Mechanism of action of Doxorubicin: inhibits both DNA and RNA synthesis by an effect on topoisomerase II (DNA gyrase) Given by i.v. infusion Epirubicin is less cardiotoxic than doxorubicin. Mitoxantrone has dose-related cardiotoxicity . Dactinomycin: Mechanism : it intercalates in the minor groove of DNA and interferes with the movement of RNA polymerase and thus prevents transcription.

Red urine Radiation recall phenomenon – seen after many years of radiation. Epithelial damage and vesicles seen at the same site after taking drugs Most common S/E – Nausea, vomitting, diarrhoea MITOXANTRONE Same as above but cardiotoxicity is rarely seen. Associated with blue urine, blue nails, blue sclera Indication – Multiple sclerosis

MITOMYCIN C Functions as a bifunctional alkylating agent Very potent drug but causes toxicity when used systemically. So not used via systemic route. Uses Tracheal stenosis and Oesophageal stenosis Superficial bladder cancer BLEOMYCIN With the help of Fe2+ bleomycin converts O2 to free radicles and causes DNA damage. It is the only anticancer drug that can be given via any route.

Metabolized by bleomycin hydrolase which is present all over the body except skin and lung. So the main S/E is lung and skin fibrosis. It causes little myelosuppression. RADIOACTIVE IODINE : I131: Used in treatment of thyroid tumours.

TOPOISOMERASE INHIBITORS Etoposide Irinotecan Teniposide Topotecan (Topoisomerase II) (TopoisomeraseI) campothecins All drugs eliminated by kidney. Caution in CRF Except Irinotecan which is a drug metabolized by liver to active SN38 which is eliminated by kidney. Cholinergic properties – diarrhoea present since day 1 of therapy. USE – colorectal carcinoma.

Hormones: Glucocorticoids: They have inhibitory effect on lymphocyte proliferation Used in leukemias and lymphomas Estrogens: Fosfeterol (a prodrug which is activated by acid phosphatase in prostatic tissue ) block the effect of androgens in androgen-dependent prostatic tumours. Estrogen can also be used to recruit resting mammary cells from compartment B to compartment A thus allowing greater killing efficiency of cytotoxic drugs. Progesterons: Megesterol and medroxyprogesterone have been useful in endometrial neoplasms and renal tumours.

Gonadotrophin- releasing hormone analogues: Goserelin can inhibit gonadotrophin release. Used to treat advanced breast cancer in postmenopausal women and prostate cancer. Analogue of somatostatin:octreotide is used to treat various hormone secreting tumours of the git such as VIPomas, glucagonomas, gastrinomas. These tumors express somatostatin receptors, activation of which inhibits cell proliferation and hormone secretion.

Hormone antagonists: Anti-estrogens: Tamoxifen is effective in hormone dependent breast cancer. In breast tissue, Tamoxifen competes with endogenous oestrogens for oestrogen receptors and inhibits transcription of oestrogen- responsive genes. Also has cardioprotective effect by preventing oxidation of LDL. Anti-androgens: Flutamide and cyproterone are used in prostate tumours. Adrenal hormone synthesis inhibitor: Formestane acts at a late stage of sex hormone synthesis by inhibiting enzyme aromatase. Trilostane and aminoglutethimide also inhibit sex hormone synthesis.

Miscellaneous agents: L-ASPERGINASE(Crisantaspase) Only enzyme used as anticancer drug. Metabolize aspergine to urea or ammonia Normal cells can form all aspergine on their own but cancer cells cannot form their own aspergine and depend on plasma aspergine. L-asperginase depletes plasma aspergine causing cancer cell death. USE- Leukemias S/E Hyperammonemia Protein deficiency Clotting and anticlotting factors are proteins so clotting disturbances Hupoalbuminemia

HYDROXYUREA Inhibitor of ribonucleotide reductase enzyme which converts ribose sugar to deoxyribose sugar incorporated in DNA Acts on the S phase of the cell cycle Side-effect: myelosupression

Miscellaneous agents: Imatinib mesylate: it is a small molecule which inhibits signalling pathway kinases. It inhibits platelet- derived growth factor. It also inhibits cytoplasmic kinase which is a unique factor in pathogenesis of chronic myeloid leukemia and hence licensed for the treatment of this tumour. Biological response modifiers: agents which enhance the host response. Examples: interferon γ, aldesleukin and tretinoin.

Monoclonal antibodies Rituximab: Attaches to CD20 proteins on B cells and kills B cells by complement mediated lysis or by inducing apoptosis. Use: B cell lymphoma Side effects: hypotension, chills and fever initially Hypersensitivity reaction May make cardiovascular diseases worse Trastuzumab: Binds to a protein called Her2/neu. (member of the epidermal growth factor receptor family- receptors with integral tyrosine kinase activity) Use: in some patients with breast cancer, these receptors are overexpressed Side effects : similar to rituximab

GEMTUZUMAB-OZAGAMYCIN COMBINATION MOA – DNA inhibition by formation of free radicles. CELL CYCLE SPECIFIC agents NON CELL CYCLE SPECIFIC agents G1/S –Etoposide Topoisomerase inhibitors S – Antimetabolite Hydroxyurea Alkylating agents G2/M – Etoposide Bleomycin All anticancer antibiotics except bleomycin M – vinka alkaloids taxens Ixebepilone Estramustine Platinum compounds

REGIMENS FOR DIFFERENT TUMOURS: DRUGS COAP Cyclophosphamide+Vincristine+ cytarabine+prednisolone POMP Prednisolone+Oncovin(Vincristine)+ Mtx+Purinethol(6-MP) CART Cytarabine+Asparginase+Rubidomycin(daunorubicin)+ 6-TG MOPP Mechlorethamine+Oncovin+ Procarbazine+Prednisolone VAMP Vincristine+Amethopterine(MTX)+ 6-MP+Prednisolone

MALIGNANCY FIRST LINE THERAPY SECOND LINE DRUGS Acute leukaemias VAMP Cytarabine, L-asparginase, Mtx, Doxorubicin Hodgin’s Disease MOPP Bleomycine, Procarbazine, lomustine, ifosphamide, doxorubicin Prostate carcinoma Flutamide+GnRH agonist Doxorubicin, cisplatin, cyclophophamide, 5-FU Breast carcinoma Tamoxifen, Mtx, 5-FU Prednisolone, Vincristine, Paclitaxel, cyclophosphamide, Mitoxantrone

Malignancy First line drugs Second line drugs Ovarian carcinoma Cisplatin, carboplatin, paclitaxel, cyclophosphamide, Doxorubicin Melphalan, Chlorambucil, 5-FU, Mtx, Vincristine, Topotecan Endometrial cancer Progestin, tamoxifen Doxorubicin, cisplatin Testicular tumours Mtx, bleomycin, etoposide, cisplatin, carboplatin Actinomycin, ifosfamide, doxorubicin, vinblastine, melphalan Lung cancer Cyclophosphamide, Vincristine, Doxorubicin Carboplatin, Mtx, Lomustine, topotecan, etoposide

Dealing with side effects: EMESIS: Mainly seen with cisplatin and other alkylating agents. Treatment: ondansetron or granisetron can be used Metoclopromide can also be used . But since it causes extra-pyrimidal side effects, diphenhydramine can be used instead.

MYELOSUPPRESSION Removing some of the patients bone marrow prior to giving cytotoxic drugs, purging it of the cancer cells and replacing it later Administration of Molgramostim, then harvesting stem cells from blood and multiplying them in-vitro with the relevant heomopoietic growth factors. Introducing mutated gene into the extracted bone marrow which confers multidrug resistance so that when this marrow is replaced the normal cells remain resistant to cytotoxic drugs but the cancer cells don’t .(a possibility)

Newer anti cancer targets The Ras proteins- Farnesyl transferase inhibitors are in development Tyrosine Kinase : Agents interfering with the epidermal growth factor receptor tyrosine kinase activity can be developed. Cyclin and cyclin dependent kinases: Flavopiridol Telomerase inhibitors Angiogenesis and matrix metalloproteinase inhibitors: Cyclo-oygenase inhibitors: COX-2 is overexpressed in many cancer cells. Cox-2 inhibitor celecoxib has shown to reduce mammary tumours in animal models. P53 gene: cancer cells carry a mutated p53 gene Antisense oligonucleotides: inhibit gene expression in tumour cells.Example : augmerosen downregulates Bcl-2

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