ANTI- CANCER DRUGS

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ANTI- CANCER DRUGS:

ANTI- CANCER DRUGS By- Dr. Sushrut Varun Satpathy 3 rd year PG Deptt . Of Clinical Pharmacology Moderator- Dr. Chandrakala Sharma Assoc. Professor Clinical pharmacology SMIMS

Protocol - :

Protocol - Origin of cancer chemotherapy Introduction Goals of therapy Classification General principles of chemotherapy Cell cycle and clinical importance Individual drugs – Alkylating agent- Nitrogen mustards, triazines , platinum coordination complexes Antimetabolites – Mtx , purine analogues, pyrimidine analogues Mitotic spindle inhibitor Anti-tumor antibiotics Targeted Drugs Hormones and related agents Resistance to anti-cancer drugs

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The origin of cancer chemotherapy..... WW (I) exposure to mustard gas led to the observation that alkylating agents caused marrow and lymphoid hypoplasia which was further studied during WW(II) This observation led to the direct application of such agents to patients with Hodgkin’s disease and lymphocytic lymphomas at Yale Cancer Center in 1943 Luis Goodman and Alfred Gillmen demonstrated it for the first time.

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1948, Sydney Farber successfully used Antifolates to induce remission in children with ALL. 1955 , National chemotherapy program begins at National cancer institute, a systematic programme for drug screening. 1958, Roy Hertz and Min Chiu Li demonstrated Methotrexate as a single best agent for choriocarcinoma , the first solid tumour that can be cured by chemotherapy. 1959, FDA approved the alkylating agent, Cyclophosphamide

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1965, The era of combination chemotherapy begins. # POMP ( Methotrexate,Vincristine,6MP,Prednisolone) regimen was able to induce long term remission in children with ALL # MOPP (Nitrogen Mustard,Vincristine,Procarbazine,Prednisolone) regimen successfully cured HL and NHL used by Vincent DeVita and collegues in 1970 Currently, nearly all successful cancer chemotherapy regimens use this paradigm of multiple drugs given simultaneously, called  combination chemotherapy or polychemotherapy .

Introduction :

Introduction Cancer (Malignant neoplasm) is a class of diseases in which a group of cells display uncontrolled growth, invasion, and sometimes metastasis As a single entity, Cancer – biggest cause of mortality worldwide – estimated 8.2 million deaths from cancer in 2012 (WHO) Cancer cases worldwide are forecast to rise by 75% and reach close to 25 million over the next two decades

Types of tumors :

Types of tumors

Goals of Therapy:

Goals of Therapy Cure or induce prolonged ‘remission’ so that all macroscopic and microscopic features of the cancer disappear, though disease is known to persist - Acute Lymphoblastic Leukaemia, Wilm`s tumor, Ewing`s sarcoma etc. in children, Hodgkin`s lymphoma, testicular teratoma and choriocarcinoma Palliation: Shrinkage of evident tumour, alleviation of symptoms and prolongation of life - Breast cancer, ovarian cancer, endometrial carcinoma, CLL, CML, small cell cancer of lung and Non-Hodgkin lymphoma

contd.:

contd. Adjuvant therapy: One of the main basis of treatment now For mopping up of residual cancer cells including metastases after Surgery, Radiation and immunotherapy etc. Routinely used now Mainly in solid tumours Insensitive or less sensitive but life may be prolonged - Cancer esophagus, cancer stomach, sq. cell carcinoma of lung, melanoma, pancreatic cancer, myeloma, colorectal cancer

Classification - :

Classification - A . Alkylating agents Nitrogen mustards – Mechlorethamine ( Mustine HCL), Cyclophosphamide , Ifosfamide , Melphalan , Chlorambucil Ethylenimine - Thio -TEPA, hexamethylmelamine ( Altretamine ) Alkyl sulfonate – Busulfan 4. Nitrosoureas – Carmustine , Lomustine , Streptozocin 5. Triazines - Procarbazine , Dacarbazine , Temozolomide

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2. Platinum coordination complexes – Cisplatin , Carboplatin,Oxaliplatin 3. Antimetabolites – Pyrimidine analogs – 5-Fluorouracil , Cytarabine (cytosine arabinoside ), Capecitabine , Gemcitabine Purine analogs – 6-Mercaptopurine, 6-Thioguanine, Azathioprine , Fludarabine , Cladribine , Pentostatin Folic acid analog – Methotrexate , Pemetrexed

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4. Microtubule damaging agents – Vincristine ( Oncovin ), Vinblastine , Vinorelbine , Paclitaxel , Docitaxel , Estramustine 5. Topoisomerase-2 inhibitors – Etoposide,Teniposide 6. Topoisomerase-1 inhibitors- Topotecan , Irinotecan 7. Antibiotics – Actinomycin D ( Dactinomycin ), Doxorubicin, Daunorubicin ( Rubidomycin ), Epiburicin , Mitoxantrone,Bleomycins , Mitomycin C

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8. Miscellaneous – Hydroxyurea , L- Asparaginase , Tretinoin , Arsenic trioxide B. Targeted Drugs – 1. Tyrosine Protein Kinase Inhibitors – Imatinib , nilotinib 2. EGF receptor inhibitors – Geftinib , Erlotinib,Cetuximab 3. Angiogenesis Inhibitors – Bevacizumab , Sunitinib 4. Proteasome Inhibitor – Bortezomib 5. Unarmed monoclonal antibody – Rituximab , Trastuzumab

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C. Hormonal drugs – Glucocorticoids – Prednisolone and others Estrogens – Fosfestrol , Ethinylestradiol Selective estrogen receptor modulators- Tamoxifen,Toremifene Selective estrogen receptor down regulators – Fulvestrant Aromatase Inhibitors – Letrozole , Anastrozole , Exemestane Antiandrogens – Flutamide,Bicalutamide 5- α reductase Inhibitors – Finasteride , Dutasteride GnRH analogues – Nafarelin,Leuprorelin,triptorelin GnRH antagonists – Cetorelix , Ganirelix , Abarelix Progestins – Hydroxyprogesterone acetate, etc.

General Principles of Chemotherapy of Cancer:

General Principles of Chemotherapy of Cancer Analogous with Bacterial chemotherapy – differences are Selectivity of drugs is limited – because “I may harm you” No or less defence mechanism – Cytokines adjuvant now All malignant cells must be killed to stop progeny – survival time is related to no. of cells that escape Chemo attack Subpopulation cells differ in rate of proliferation and susceptibility to chemotherapy Drug regimens or combined cycle therapy after radiation or surgery (Basis of treatment now in large tumour burdens) Complete remission should be the goal – but already used in maximum tolerated dose – so early treatment with intensive regimens Formerly single drug – now 2-5 drugs in intermittent pulses – Total tumour cell kill – COMBINATION CHEMOTHERAPY

COMBINATION CHEMOTHERAPY - SYNERGISTIC:

COMBINATION CHEMOTHERAPY - SYNERGISTIC Drugs which are effective when used alone Drugs with different mechanism of action Drugs with differing toxicities Drugs with different mechanism of toxicities Drugs with synergistic biochemical interactions Optimal schedule by trial and error method More importantly on cell cycle specificity

Cell Cycle and Clinical Importance:

Cell Cycle and Clinical Importance All cells—normal or neoplastic—must traverse before and during cell division Malignant cells spend time in each phase - longest time at G1, but may vary Many of the effective anticancer drugs exert their action on cells traversing the cell cycle - cell cycle-specific (CCS) drugs Cell cycle-nonspecific (CCNS) drugs - sterilize tumor cells whether they are cycling or resting in the G0 compartment CCNS drugs can kill both G0 and cycling cells - CCS are more effective on cycling cells

Phases of cell cycle:

Phases of cell cycle G1 - primary growth phase S – synthesis; DNA replicated G2 - secondary growth phase collectively these 3 stages are called interphase M - mitosis C - cytokinesis

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21 Daughter Cells DNA Copied Cells Mature Cells prepare for Division Cell Divides into Identical cells

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Control of cell cycle- by special proteins and enzymes that act as switches G1 checkpoint- stop, pause or go into S phase some cells stop permanently G2 checkpoint- will cell divide? M checkpoint- formation of new cells

Drugs Based on Cell Cycle:

Drugs Based on Cell Cycle CCNS: Nitrogen Mustards- Cyclphosphamide , chlorambucil , carmustine , dacarbazine , busulfan , L- asparginase , cisplatin , procarbazine and actinomycin D etc. CCS: G1 – vincristine S – Mtx , cytarabine , 6-thioguanine, 6-MP, 5-FU, daunorubicin , doxorubicin G2 – Daunorubicin , bleomycin M – Vincristine , vinblastne , paclitaxel etc.

The Log-Kill hypothesis - :

The Log-Kill hypothesis - The  CELL KILL HYPOTHESIS  proposes that actions of  CCS  drugs follow  first order  kinetics:  a given dose kills a  constant PROPORTION  of a  tumor cell  population (rather than a constant  NUMBER  of cells).

Individual Drugs - :

Individual Drugs - ALKYLATING AGENTS – produce highly reactive carbonium ion intermediates which transfer alkyl groups to cellular macromolecules by forming covalent bonds – position 7 of guanine residues is susceptible Alkylation results in cross-linking/abnormal base pairing/scission of DNA strand Cytotoxic and radiomimetic (like ionizing radiations) actions CCNS – dividing + resting cells

Nitrogen Mustards:

Nitrogen Mustards Mechlorethamine ( Mustine HCl ): Uses: Hodgkin’s and Non-Hodgkin’s lymphoma Given IV Part of MOPP ( Mechlorethamine – oncovine-prednisolone and procarbazine ) in Hodgkin`s disease ADRs: Severe Vomiting, myelo and immunosuppression Extravasation – severe local toxicity Dose- 0.1 mg/kg iv daily x 4 days ; courses may be repeated at suitable intervals Cyclophosphamide : Transformed into active aldophosphamide and phospharamide Administered orally Used in Hodgkin's lymphoma, breast and ovary cancers

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Cyclophosphamide Aldophosphamide Phoshoramide Acrolein mustard ( cytotoxic effect) (toxic metabolite) Mesna (-SH compound) Dose – 2-3 mg/kg/day oral , 10-15 mg/kg i.v every 7-10 days

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IFOSFAMIDE – Congener of cyclophosphamide Longer and dose dependent T 1/2 used in bronchogenic , breast, testicular,bladder ,head and neck carcinomas Dose limiting toxicity – Haemorrhagic cystitis Mesna is a SH- compound -- excreted in urine – binds and inactivates the vesicotoxic metabolites of ifosfamide and cyclophosphamide Causes less alopecia and less emetogenic

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CHLORAMBUCIL – Slow acting alkylating agent, esp. active against lymphoid tissues myeloid tissues – largely spared (Ch. Lymphatic leukaemia and non-Hodgkin's lymphoma) Dose – 0.1-0.2 mg/kg daily for 3-6 weeks, then 2 mg daily for maintenance MELPHALAN – very effective in multiple myeloma and advanced Ovarian cancer , toxicity- BMD Thio -TEPA – ethylenimine , High Toxicity seldom used – Ovarian and Bladder Ca

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BUSULFAN – alkyl sulfonate , highly selective for myeloid elements; Granulocyte precursors(most sensitve ) > Platelets and RBC little effect on lymphoid tissue and GIT Hyperuricemia (common); Pulmonary fibrosis and skin pigmentation – specific adverse effect NITROSOUREAS – ( Carmustine etc.) highly lipid soluble, crosses BBB – meningeal leukemias and brain cancer N,V - common , CNS effects BMD –delayed -6 weeks , Visceral fibrosis and Renal damage

Triazines :

Triazines PROCARBAZINE – Not a classical alkylating agent, similar properties After metabolic activation – methylates and depolymerizes DNA – chromosomal damage Mutagenic and carcinogenic potential Component of MOPP regimen – Hodgkin’s Lymphomas DACARBAZINE – after activation in liver – methylating DNA , most imp. Indication – malignant melanoma, also – hodgkin’s lymphoma TEMOZOLAMIDE- orally active triazine methylating agent, d.o.c – glioma and other malignant brain tumours, also melanoma

Platinum Coordination Complexes -:

Platinum Coordination Complexes - CISPLATIN – Heavy metal complex , CCNS Hydrolysed intracellularly – highly reactive moiety – cross-linking DNA ( both intrastrand and interstrand ) Favored site – N7 of guanine residue Also reacts with –SH groups of cytoplasmic and nuclear proteins Effects resemble – alkylating agent and radiation Plasma protein bound, penetrates tissues Slowly excreted in urine, T1/2 – 72 hrs Highly effective – testicular, ovarian, endometrial and bladder Ca Also used in Lung and Oesphageal Ca

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Dose – Cisplatin adm . Slow i.v infusion 50-100 mg/m 2 BSA every 3-4 weeks Adverse effects – Most emetogenic anticancer drug, controlled by 5HT 3 antagonist Nephrotoxicity – can be minimized by proper hydration and chloride diuresis Ototoxicity with hearing loss can occur and is severe with repeated doses Electrolyte disturbances : Hypokalemia , Hypocalcemia and Hypomagnesemia Rarely Anaphylactic shock , Mutagenic , Teratogenic and Carcinogenic properties

Anti-Metabolites :

Anti-Metabolites Analogues related to the normal components of DNA or of coenzymes involved in nucleic acid synthesis Competitively inhibit utilization of the normal substrate or get themselves incorporated forming dysfunctional macromolecules Folic acid analogue – Mtx , Pemetrexed Purine analogue – 6-MP, 6-TG, Fludarabine , Cytarabine , pentostatin Pyrimidine analogue – 5-Fluorouracil , Cytarabine (cytosine arabinoside ), Capecitabine , Gemcitabine

Methotrexate(Mtx) – Folate antagonist:

Methotrexate ( Mtx ) – Folate antagonist Most commonly and oldest anticancer drug CCS drug Acts during S phase of the cell cycle Antineoplastic , immunosuppresant and anti-inflammatory effects Mtx structurally resembles folic acid – competitively inhibits dihydrofolate reductase enzyme and prevents the conversion of DHFA to THFA – depletes intracellular THFA THFA necessary for synthesis of purines and thymidylate – DNA and RNA synthesis Utilizing the folate carrier – enters the cells – transformed into more active polyglutamate form by enzyme folypolyglutamate synthase (FPGS)

M.O.A:

M.O.A Methotrexate Dihydrofolate reductase Dihydrofolic acid Tetrahydrofolic acid (DHFA) (DHFR) (THFA) Leucovorin synthesis of purines Folinic acid and thymidylate (N 5 formyl FH 4 ) Citrovorum factor DNA and RNA synthesis

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Mtx well absorbed after oral adm . , can be given i.m , i.v or intrathecally 50% bound to plasma proteins Poorly crosses BBB and most of the drug excreted unchanged in urine d.o.c – choriocarcinoma ; 15-30 mg/day for 5 days orally or 20-40 mg/m 2 BSA i.m or i.v twice weekly Also used in Acute leukemias , Burkitt’s Lymphoma and Breast Ca. Low dose Mtx ( 7.5-30 mg once weekly) – R.A Other Uses – Psoriasis, IBD and in Organ transplantataion

Folinic acid rescue/ Leucovorin rescue - :

Folinic acid rescue/ Leucovorin rescue - Toxic effects of Mtx on normal cells can be minimized by giving folinic acid Availabilty of folinic acid has helped the use of very high doses of Mtx for better antineoplastic effect A nearly 100 times higher dose (250-1000 mg/m 2 BSA) of Mtx infused i.v over 6 hrs, followed by 3-15 mg i.v calcium leucovorin within 3 hrs, repeated as required Can be repeated weekly Folinic acid (Active CoA ) – bypasses the block produced by Mtx and rapidly reverses the toxicity

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Resistance: Reduction of affinity of DHFR to MTX Diminished entry of MTX into cancer cells Over production of DHFR enzyme

Pemetrexed :

Pemetrexed Newer congener of Mtx Primarily targets the enzyme Thymidylate synthase Though not a DHFRase inhibitor, the pool of THFA is not markedly reduced Like Mtx , it utilizes the folate carrier to enter cells and requires transformation into polyglutamate form by FPGS for activity enhancement Adverse effects – Mucositis , Diarrhoea , Myelosuppression (same as Mtx ) painful, itching erythematous rash, mostly involving the hands and feet ‘hands foot syndrome’ – common Dose – 500 mg/m 2 i.v every 3 weeks

Purine analogues - :

Purine analogues - 6-MERCAPTOPURINE and 6-THIOGUANINE – Highly effective anti- neoplastic drugs synthesis in the body into corresponding Monoribonucleotides – inhibit the conversion of Inosine monophosphate to adenine and guanine nucleotides – building blocks for DNA and RNA Also – feedback inhibition of de novo purine synthesis, get incorporated into RNA and DNA – dysfunctional Esp. useful – childhood acute leukemias , choriocarcinoma and few solid tumors Absorbed orally , poor penetration BBB

Cont…6-MP and 6-TG:

Cont…6-MP and 6-TG Azathioprine and 6-MP oxidised by xanthine oxidase Allopurinol xanthine oxidase 6-Mercaptopurine 6-Thiouric Acid Dose reduced to 1/4 th to 1/2 nd if allopurinol is given concurrently Thioguanine not a substrate for xanthine oxidase – (s- methylation )

Cont…6-MP and 6-TG:

Cont…6-MP and 6-TG Methylation by TPMT is an additional pathway of 6-MP metabolism Genetic def. of TPMT makes individual more susceptible to 6-MP induced myelosuppression , mucositis and gut damage, while overexpression of TPMT is an important mechanism of 6-MP resistance in acute leukemia cells BMD- major adverse effect of 6-MP Dose – 6-MP - 2.5 mg/kg/day, half dose for maintenance 6-TG – 100-200 mg/m 2 /d for 5-20 days

Fludarabine -:

Fludarabine - Newer purine anti-metabolite – phosphorylated intracellularly – active triphosphate form – inhibits DNA polymerase and ribonucleotide polymerase – interferes with DNA repair as well as gets incorporated to form dysfunctional DNA Indicated in Chronic Lymphatic Leukemia and Non-Hodgkin’s lymphoma that have recured after treatment Adverse effects – chills, fever, myalgia , arthralgia and vomitting after injection, myelosuppression and oppurtunistic infections Dose – 25 mg/m 2 BSA daily for 5 days every 28 days by i.v infusion

Pyrimidine analogues - :

Pyrimidine analogues - FLUOROURACIL (5-FU) – Mechanism of action - Fluorouracil FdUMP Thymidylate synthetase dUMP TMP DNA synthesis

5-FU cont….:

5-FU cont …. Uses – colorectal , upper GIT, breast and ovarian Oral absorption of 5-FU is unreliable , primarily used by i.v infusion 5-FU rapidly metabolized by dihydropyrimidine dehydrogenase (DPD) resulting in a plasma T1/2 15-20 mins after i.v infusion Genetic deficiency of DPD – severe 5-FU toxicity A/Es – myelosuppression , mucositis , diarrhoea , nausea and vomitting , peripheral neuropathy (hand-foot syndrome)

Pyrimidine analogues…cont…:

Pyrimidine analogues…cont… CYTARABINE (Cytosine arabinoside ) – Cytidine analogue Single most effective agent for induction of remission in AML Drug is activated by kinases to AraCTP – inhibitor of Dna polymerases Of all antimetabolites – Cytarabine is the most specific for the S phase of the cell cycle Resistance to cytarabine can occur either due to decreased uptake or decraesed conversion to AraCTP High dose – Neurotoxicity ( Ataxia and peripheral neuropathy)

Pyrimidine analogues…cont…:

Pyrimidine analogues…cont… GEMCITABINE – Deoxy-Cytidine analogue – converted – active diphosphate and triphopshate nucleotide form Gemcitabine diphosphate – inhibits ribonucleotide reductase – diminish pool of deoxyribonucleoside triphosphates required for DNA synthesis Can be incorporated into DNA – chain termination PK- elimination mainly by metabolism Clinical use- initially Pancreatic Ca , nowadays widely – Non-Small Cell Lung Ca, Bladder Ca., and Non- hodgkin’s lymphoma

Mitotic Spindle Inhibitors / Natural Product Anticancer Drugs - :

Mitotic Spindle Inhibitors / Natural Product Anticancer Drugs - Most imp. of these plant derived, CCS drugs are Vinca alkaloids( vinblastine , vincristine , vinorelbine ), podophyllotoxins ( etoposide , teniposide ), the camptothecins ( topotecan,irinotecan ), the taxanes ( paclitaxel , docetaxel ) VINKA ALKALOIDS – Vinblastine and Vincristine are derived from the periwinkle plant CCS agent , act during M phase of the cycle Block the formation of Mitotic Spindle by preventing the assembly of tubulin dimers into microtubules

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M.O.A – Vinblastine and Vincristine Bind to β - tubulin (drug tubulin complex) inhibits its polymerization into microtubules No intact mitotic spindle cell division arrested in metaphase

Vinca alkaloids – cont..:

Vinca alkaloids – cont.. PK - given parenterally , penetrate most tissues except CSF cleared mainly via biliary secretions Clinical use – Vincristine - Acute leukemias , lymphomas, Wilm’s Tumor and Neuroblastoma Vinblastine – Lymphomas,Neuroblastomas, Testicular ca.and Kaposi’s sarcoma Vinorelbine – non-small cell lung carcinoma and breast Ca . Toxicity – Vinblastine and Vinorelbine cause GI distress, Alopecia and bone marrow suppression Vincristine is ‘marrow sparing’ but neurotoxic

Natural Product Anticancer Drugs –cont….:

Natural Product Anticancer Drugs –cont…. ETOPOSIDE and TENIPOSIDE – Etoposide , a semisynthetic derivative of podophyllotoxin,induces DNA breakage through its inhibiton of topoisomerase ІІ Most active in late S and early G 2 phase of the cell cycle Teniposide is an analogue with similar properties PK- orally well absorbed and distributes to most body tissues Elimination is mainly via kidneys Clinical use – Testicular and lung ca. in combination with cytotoxic agents. Non- hodgkin’s lymphoma and AIDS related Kaposi’s Sarcoma

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Etoposide and Teniposide forms complex with DNA and topoisomerase ІІ prevent resealing of broken DNA strand Cell death Toxicity – Etoposide and Teniposide are GI irritants and cause alopecia and bone marrow suppression

Natural Product Anticancer Drugs –cont….:

Natural Product Anticancer Drugs –cont…. TOPOTECAN and IRINOTECAN – Obtained from camptotheca acuminata tree 2 camptothecins , Topotecan and Irinotecan , produce DNA damage by inhibiting Topoisomerase І PK- Irinotecan – prodrug – converted to active metabolite in liver , Topotecan is eliminated renally , whereas Irinotecan and its metabolite eliminated in bile and faeces Clinical use – Topotecan - 2 nd line agent – Advanced Ovarian Ca and for small cell lung Ca. Irinotecan – Metastatic Colorectal Ca Toxicity – Myelosuppression and Diarrhoea

Natural Product Anticancer Drugs –cont….:

Natural Product Anticancer Drugs –cont…. TAXANES – Paclitaxel , docetaxel Derived from the bark of the western yew tree Paclitaxel binds to β - tubulin stabilizes microtubules formation of abnormal microtubules inhibits mitosis Prevent microtubule disassembly into tubulin monomers Given I.V Advanced breast, ovarian , lung, oesophageal and bladder ca. Paclitaxel-neutropenia,thrombocytopenia,high incidence of peripheral neuropathy and possible hypersensitvity reaction Docetaxel cause neurotoxicity and BMD

Antitumor antibiotics - :

Antitumor antibiotics - Made up of several structurally dissimilar microbial products and includes the anthracyclines , bleomycin and mitomycin ANTHRACYCLINES – Doxorubicin, daunorubicin , idarubicin , epirubicin , mitoxantrone Intercalate between base pairs, inhibit Topoisomerase ІІ , and generate free radicals Block synthesis of RNA and DNA – cause DNA strand scission, membrane disruption also occurs Anthracyclines CCNS drugs

Anti-tumor antibiotics…cont…:

Anti-tumor antibiotics…cont… Doxo and Daunorubicin must be given IV Metabolized in liver , excreted in bile and urine Doxorubicin – hodgkin’s and non- hodgkin’s lymphoma ,myelomas , sarcomas, breast, lung, ovarian and thyroid ca. Daunorubicin – acute leukemias Idarubicin – AML Epirubicin – breast and gastro- esphageal ca Mitoxantrone –AML, non- hodgkin’s lymphoma, breast ca and gastro-esophageal ca Toxicity - BMD,GI distress and severe alopecia Distinctive a/e – cardiotoxicity - dexrazoxane (free radical scavenger) and α - tocopherol

Anti-tumor antibiotics…cont…:

Anti-tumor antibiotics…cont… BLEOMYCIN – CCS glycopeptide , acts in the G2 phase- generates free radicals – bind to DNA – DNA strand breaks – inhibit DNA synthesis Given parenterally , inactivated by tissue aminopeptidases mainly Testicular and Ovarian tumors, Hodgkin’s lymphoma (ABVP regimen) Toxicity – Pulmonary dysfunction ( pneumonitis , fibrosis) cutaneous toxicity ( hyperpigmentation,hyperkeratosis,erythema and ulcers)

Anti-tumor antibiotics…cont…:

Anti-tumor antibiotics…cont… MITOMYCIN-C CCNS , metabolized by liver enzymes – forms an alkylating agent – crosslinks DNA Mitomycin given intravenously and is rapidly cleared by hepatic metabolism Uses- mitomycin act against hypoxic tumor cells and used in combination regimens for adenocarcinomas of the cervix, stomach,pancreas and lung Can be used as intravesical therapy to treat superficial bladder ca and anal ca (with radiation therapy) Toxicity – BMD, GI distress and Nephrotoxicity

Targeted drugs - :

Targeted drugs - TYROSINE KINASE INHIBITORS – Imatinib , geftinib,erlotinib,sorafenib,sunitinib,lapatinib etc . IMATINIB- Selective anti-cancer drug whose development was guided by knowledge of specific oncogene Inhibits tyrosine kinase activity of protein product of bcr-abl oncogene (t9,22; philadelphia chromosome) that is commonly expressed in CML

IMATINIB- :

IMATINIB- First selectively targeted drug to be introduced Inhibits a specific tyrosine protein kinase – “ Bcr-abl ” tyrosine kinase expressed by CML cells and related receptor tyrosine kinases including PDGF receptor that is constitutively active in dermatofibrosarcoma protuberans , stem cell receptor and c-kit receptor active in GIST Very sucessful in chronic phase of CML (remission> 90%) and in metastatic c-kit (+) GIST . Also indicated in Dermatofibrosarcoma protuberans Resistance develops mainly due to point mutation in Bcr-Abl tyrosine kinase

IMATINIB- cont…:

IMATINIB- cont… PK- well absorbed orally , metabolized in liver , one active metabolite also produced metabolised mainly by CYP3A4 , metabolites excreted in faeces through bile T1/2 – 18 hrs while that of its active metabolite is double A/Es- Abdominal pain, vomitting , fluid retention,periorbital oedema,pleuarl effusion,myalgia and CHF Dose – 400 mg/day with meals; accelerated phase of CML – 600-800 mg/day Dasatinib and Nilotinib are similar drugs used in case of Imatinib resistance

EGF receptor inhibitors - :

EGF receptor inhibitors - GEFTINIB – EGF – transmembrane receptor-tyrosine- kinase regulates growth and diffrentiation of epithelial cells Binding of ligand (EGF) to extracellular domain of receptor induces dimerization leading to activation of tyrosine kinase activity of intracellular domain

Geftinib …cont…:

Geftinib …cont… a utophosphorylation of the kinase and phosphorylation of several cytoplasmic regulatory proteins which modify gene transcription to regulate growth Geftinib – binds to tyrosine kinase domain of EGF receptor ( Erb β 1, or HER1 )- prevents phosphorylation of regulatory proteins Indicated for Non-small cell lung Ca .(EGFR activating mutation) Oral bioavailability – 60% , primarily meatbolized by CYP3A4 T1/2 – 40 hours Dose – 250 mg/day orally

EGF receptor inhibitors…cont..:

EGF receptor inhibitors…cont.. Others- Erlotinib also indicated for Pancreatic Ca with Gemcitabine Sorafenib and Sunitinib are small molecules that inhibit multiple tyrosine kinases – both can be used for RCC, sorafenib - hepatocellular ca and sunitinib - GIST , A/e – hypertension Lapatinib – Breast ca. (-) tyrosine kinase assoc. with EGFR and her-2/ neu receptors Pazopanib is to form multi targeted tyrosine kinase inhibitor against VEGF receptors, PDGF receptors and c-kit, approved for advanced RCC

Monoclonal antibodies - :

Monoclonal antibodies - Monoclonal Abs Targeted against Indication Comments Rituximab CD-20 Non- hodgkin’s lymphoma Alemtuzumab CD-52 Low grade lymphomas and CLL Trastuzumab HER 2/ neu Breast Ca Can cause cardiotoxicity Cetuximab and Panitumumab EGFR EGFR-positive metastatic colorectal carcinoma Rash, hypomagnesemia and interstitial lung disease Bevacizumab VEGF Metastatic colorectal ca Combined with 5-FU

Hormones and related agents - :

Hormones and related agents - GLUCORTICOIDS – Prednisolone - most commonly used glucorticoid in Ca.chemo . Used for combination chemotherapy in leukemia and lymphomas ESTROGEN – Physiological antagonists of androgens Antagonizes the effects of androgens in androgen dependent prostatic tumors- fosfestrol ( prodrug ) – stilboestrol (prostatic tissue) TAMOXIFEN- Anti- oestrogen mainly used in the palliative treatment in hormone dependent breast ca

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PROGESTINS – Medroxyprogesterone acetate, hydroxyprogesterone caproate and megestrol 2 nd line hormonal therapy for metastatic hormone dependent breast ca and endometrial ca ANTI-ANDROGENS – Flutamide and bicalutamide – bind to androgen receptor – inhibit androgen actions Prostatic ca, used along with GNRH agonist – strategy known as ‘complete androgen blockade’ Flutamide can cause – hot flushes, hepatic dysfunction and gynaecomastia

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GnRH agonists - Goserelin , Nafarelin and leuprolide act as agonist of GnRH used in advanced prostatic ca A/e- flaring up of disease, hot flushes,impotence,gynaecomastia and osteoporosis GnRH antagonist – Cetrorelix , ganirelix and abarelix are antagonist of GnRH Decrease the release of gonadotropins without causing initial stimulation Can be used in prostatic ca without the risk of flare up reaction

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AROMATASE Inhibitors – Anastrozole , letrozole etc Aromatase is the enzyme responsible for conversion of androstenedione ( androgen precursor) to estrone (estrogenic hormone) 1 st gen.- aminoglutethimide 2 nd gen.- formestane , fadrozole,rogletimide 3 rd gen.- exemestane,letrozole,anastrozole Aromatase inhibitors – useful in advanced breast ca . Adverse effects – hot flushes, arthralgia and fatigue

Other anticancer drugs - :

Other anticancer drugs - L- Asparaginase – Enzyme used for treatment of leukemias and lymphomas These tumors require exogenous asparagine for growth L- asparaginase acts by depleting this amino acid in serum Adm. by IV route a/e – hypersensitivity reactions, acute pancreatitis and cortical vein thrombosis Pentostatin – Used for treatment of hairy cell leukemia Acts by inhibiting – adenosine deaminase

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OCTREOTIDE – Long acting somatostatin analogue Useful in treatment of islet cell ca (decreases both insulin and glucagon secretion) Other uses – secretory diarrhoea , esophageal varices and acromegaly PLICAMYCIN – Used for hypercalcemia of malignancy and metastatic testicular ca

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HYDROXYUREA – ( sickle cell anaemia , essential thrombocytosis and polycythemia vera ) Can also be used in CML – Acts by inhibiting ribonucleoside reductase (rate limiting step in synthesis of DNA) TRETINOIN (ATRA) – All trans retinoic acid –induces 70% or more rate of complete remission in acute promyelocytic leukemia Can cause various types of toxicity – Vit A toxicity, retinoic acid syndrome, CNS toxicity, Hyperholesterolemia , hypertriglyceridemia

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As 2 O 3 – Used for treatment of acute promyelocytic leukemia (APML) May cause hyperglycemia and prolonged QT interval Bortezomib – Acts by inhibiting proteasome resulting in down regulation NF- k B ( involved in cell survival) used – resistant multiple myeloma

Resistance to anticancer drugs - :

Resistance to anticancer drugs - Drug resistance is a major problem in cancer chemotherapy. Mechanism of resistance includes the following – Increased DNA repair – An increased rate of DNA repair in tumor cells can be responsible for resistance and is particularly important for alkylating agents and cisplatin Formation of trapping agents – some tumor cells increase their production of thiol trapping agents ( eg . glutathione), which interact with anticancer drugs that form electrophillic species. This mechanism of resistance is seen with alkylating agent, bleomycin , cisplatin and anthracyclines

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3. Changes in target enzymes – changes in drug sensitivity of a target enzyme, dihydrofolate reductase , and increased synthesis of the enzyme are mechanisms of resistance of tumor cells to methotrexate 4. Decreased activation of pro-drugs – resistance to the purine antimetabolites (6-MP,6-TG) and the pyrimidine anti-metabolite (cytarabine,5-FU) can result from a decrease in the activity of tumor cell enzymes needed to convert these prodrugs to their cytotoxic metabolites

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5. Inactivation of anticancer drugs- increased activity of enzymes capable of inactivating anticancer drugs is a mechanism of tumor cell resistance to most of the purine and pyrimidine anti-metabolites 6. Decreased drug accumulation – this form of multi-drug resistance involves the increased expression of a normal gene (MDR1) for a cell surface glycoprotein (P-glycoprotein). This transport molecule is involved in the accelerated efflux of many anticancer drugs in resistant cells

References- :

References-  WHO  Global Health  Observatory. Available at:  http://www.who.int/gho/map_gallery/en/ City Mayors. Available at:  http://www.citymayors.com/statistics/largest-cities-population-125.html Tripathi KD, Anticancer drugs , Chemotherapy of neoplastic diseases; 7 th ed ; 857-877 Katzung’s and Trevor’s, Pharmacology: Examination and board review, Cancer chemotherapy, 10 th ed. 465-475 Goodman and Gillman’s 12 th ed. Images www.google.com , images

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Chemosensitivity of tumors high ALL Hodgkin’s disease NHL testicular cancer SCLC Wilms’ tumo r medium ovarian cancer breast cancer osteosarcoma head & neck cancer multiple myeloma bladder cancer colorectal cancer low NSCLC cervical cancer endometrial cancer adult soft tissue sarcoma malignant melanoma liver cancer pancreatic cancer

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