anticancer drugs

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Pharmacology of anticancer drugs

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Anticancer Drugs:

Anticancer Drugs Dr.S.P.Dhanya Assistant Professor Govt TDMCA

Slide 3:

Genetic disease Intrinsic error in DNA replication

Cell cycle:

G 0-Resting Cell cycle

Characteristics:

Characteristics Uncontrolled proliferation-resistance to apoptosis Lack of differentiation-Non functional cells Local invasiveness & metastasis Where is cancer common? Bone marrow , gastrointestinal ,skin cells ….multiply constantly Certain cells don’t divide-lens, cardiac myocyte

Modalities for treatment of cancer:

Modalities for treatment of cancer Surgery Radiotherapy Chemotherapy Endocrine therapy Immunotherapy

Objectives of treatment:

Objectives of treatment To provide care- choriocarcinoma , leukemia To palliate-not curable-avoid toxic regimen The history of sulphur mustard

Characteristics of anticancer drugs:

Characteristics of anticancer drugs Highly toxic with low therapeutic index Lack selectivity Natural host defense –not working Follows first order kinetics- constant fraction of cells are killed in unit time so we cant produce a total cell kill Rapidly dividing cells are more sensitive to treatment If resistance develops-it will be totally non-responsive High cost

Principles of treatment:

Principles of treatment Weigh Risk and Benefit All anticancer drugs are highly toxic CURE-go for toxic regimens PALLIATION-less toxic Before starting the treatment ensure that the patient is fit for treatment Treat sensitive tumors as early as possible Use combination therapy-?

Slide 13:

Chemotherapy-high dose intermittent Drug free holidays-help normal tissue to recover Adjuvant chemotherapy is given to knock off the micrometastais

Classification:

Classification Cytotoxic drugs Targeted drugs Hormonal Drugs

Cytotoxic drugs:

Cytotoxic drugs 1.Alkylating agents Nitrogen mustards Cyclophosphamide Ifosfamide Mechlorethamine Chlorambucil Melphalan Thiotepa Busulfan Carmustine Lomustine Dacarbazine Procarbazine Temozolamide

Platinum Coordination Complex:

Platinum Coordination Complex Cisplatin Carboplatin Oxaliplatin

2.Antimetabolites:

2.Antimetabolites Folate antagonists- Methotrexate,Pemetrexed Purine antagonists-6-Mercaptopurine, 6 Thioguanine , Azathioprine,Fludarabine Pyrimidine antagonist-5-Fluorouracil, Capecitabine , Cytarabine (cytosine arabinoside )

3.Natural products:

3.Natural products A. Microtubule damaging agents Vincalkaloids - Vincristine , Vinblastine , Vinorelbine Taxanes-Paclitaxel , Docetaxel Estramustine

B. Topoisomerase inhibitors:

B. Topoisomerase inhibitors Topoisomerase 1 i Camptothecins-Topotecan,Irinotecan Topoisomerase 2 I Epipodophyllotoxins-Etoposide,Teneposide

C. Anticancer Antibiotics:

C. Anticancer Antibiotics Actinomycin D Doxorubicin Daunorubicin Epirubicin Mitoxantrone Bleomycin Mitomycin C

4. Miscellaneous:

4. Miscellaneous Hydroxyurea L- asparginase Retinoids-Tretinoin,Isotretinoin Arsenic trioxide Thalidomide

Classification:

Classification Cytotoxic drugs Targeted drugs Hormonal Drugs

Targeted drugs:

Targeted drugs Tyrosine pr kinase i - Imatinib , Nilotinib EGF receptor i - Gefitinib , Erlotinib Angiogenesis inhibitors- Bevacizumab,Sunitinib Proteasome inhibitors - Bortezomib Monoclonal Ab - Rituximab,Trastuzumab

Classification:

Classification Cytotoxic drugs Targeted drugs Hormonal Drugs

Hormonal drugs:

Hormonal drugs Glucocoticoids - Prednisolone Estrogens - Fosfosterol,Ethinylestradiol SERM - Tamoxifen , Toremifene SERD - Fulvestrant Aromatase i - Letrozole,Anastrazole , Exemestane Antiandrogen - Flutamide , Bicalutamide 5 alpha reductase - Finasteride , Dutasteride GnRH analogues - Nafarelin,Leuprorelin,Triptorelin Progestin - Hydroprogesterone

Cell cycle:

Cell cycle S Hydroxyurea Antimetabolites Camptothecins G2 Bleomycin M Taxanes Vinca alkaloids G1-L-asparaginase G0 CCNS- Alkylating agents Antibiotics Procarbazine

Toxicities in General :

Toxicities in General Highly toxic-act on normal cells GI, Bone marrow, gonads, skin Low therapeutic index Bone marrow, skin, GI mucosa, lymphoreticular , gonads

Bone marrow suppression:

Bone marrow suppression Most important and serious Bone marrow suppression Dose limiting and serious ADR 10-14 days bone marrow suppression---recover within 4-6 weeks Delayed BM suppression Nitrosureas Mitomycin Least toxicity with L- asparaginase Bleomycin

Anemia,Infection,Bleeding:

Anemia,Infection,Bleeding Suppression of CMI and Humoral Immunity Opportunistic infections like candida Antibiotics Blood transfusion Recombinant erythropoietin Oprelvekin

Alopecia:

Alopecia Damage to hair follicles Cyclophosphamide Doxorubicin Daunorubicin Paclitaxel Vincristine Less toxic-L- Asparaginase,Cisplatin Hair starts growing after 4-6 weeks

GI:

GI Nausea and vomiting Cisplatin Doxorubicin Mustine Dacarbazine Less with L- asparaginase Treatment- Ondansetron Diarrhoea and Mucositis - Bleomycin , Actinomycin D, Daunorubicin , Doxorubicin, Fluorouracil

Gonads:

Gonads Oligozoospermia Impotence in males Inhibition of ovulation Amenorrhoea Mutagenesis

Foetus:

Foetus Abortion Foetal death Teratogenesis Impaired growth

Carcinogenicity:

Carcinogenicity Secondary cancers Leukemias Lymphomas

Hyperuricemia:

Hyperuricemia Massive destruction of cell In leukemia and bulky lymphoma Acute renal failure, gout,urate stones

Slide 36:

Neuropathy- vincristine,oxaliplatin Cardiomyopathy-doxorubicin,daunorubicin Cystitis - cyclophosphamide,ifosfamide Stomatitis oral ulceration-5 FU,Methotrexate Pulmonary fibrosis- Bleomycin,Busulfan Disulfiram like reaction- Procarbazine Nephrotoxicity-Cisplatin

Treatment:

Treatment 1.CSF-Reduce bone marrow suppression GCSF- Filgrastim,Lenograstim GM-CSF- Sargramostim,Molgramostim Erythropoeitin , Darbopoetin,Thrombopoeitin 2.Amifostine-thiol-scavenge free radicals and superoxides -Reduce nephrotoxicity 3.MESNA-Acrolein conjugator -Reduce cystitis 4.Dexrazoxane-Reduce cardiotoxicity 5.Oprelvekin-rIL-11,for thrombocytopenia-t1/2-1wk

***6.Folinic acid/Leucovorin rescue*** :

***6.Folinic acid/ Leucovorin rescue*** Folinic acid rescue permitted administration of > 100 fold dose of Methotrexate Normal cells are rescued more than the cancer cells Therapeutic index is increased.

***Why combination ???***:

***Why combination ???*** 2–5 drugs --achieve total tumour cell kill intermittent pulses- time for normal cells recovery Rationale (a) Drugs which are effective when used alone. (b) Drugs with different mechanisms of action. (c) Drugs with differing toxicities. (d) Drugs with different mechanisms of resistance. (e) Empirically by trial and error. (f) Drugs with known synergistic biochemical interactns (g) Kinetic scheduling: Basis of CCS/CCNS

Alkylating Agents:

Alkylating Agents Highly reactive carbonium ion intermediates Transfer alkyl group-covalent bond Position 7-guanine in DNA Cross linkage-Abnormal base pairing-Scission of DNA strand Cross linking of nucleic acid with proteins Cytotoxic and radiomimetic action CCNS

Mechlorethamine:

Mechlorethamine First nitrogen mustard Highly reactive and local vesicant Can be given orally by intravenous route Nausea,vomiting,hemodynamic changes Extravasation -sloughing Indications-HL,NHL

****Cyclophosphamide****:

**** Cyclophosphamide **** Most popular Inactive-Transformation- aldophosphamide , phosphoramide mustard Wide range of antitumor action Immunosuppressant property Useful in many solid tumors Acrolein -Alopecia and cystitis are prominent

***Ifosfamide***:

*** Ifosfamide *** Congener of cyclophosphamide Longer and dose dependent t1/2 Iess alopecia and less emetogenic than cyclophosphamide Hemorrhagic cystitis Utility in bronchogenic,breast,testicular,bladder,head and neck carcinomas,osteogenic sarcoma and some lymphomas

****Treatment of cystitis***:

****Treatment of cystitis*** 1.MESNA-SH compound excreted in urine 2. Irrigating the bladder with acetylcysteine Binds and inactivates the vasicotoxic metabolites of ifosfamide and cyclophosphamide 3. Generous fluid intake and frequent bladder voiding also helps.

Slide 45:

Chlorambucil -for Lymphoid tissue Long term maintenance----c/c lymphatic leukemia Busulfan -For myeloid elements c/c myeloid leukemia Pulmonary fibrosis ,Hyperuricemia,Skin pigmentation Melphalan - In Multiple myeloma Important toxicity-Bone marrow depression

Nitrosureas:

Nitrosureas Carmustine Lomustine Highly lipid soluble-cross blood brain barrier- meningeal leukemia and brain cancer Delayed BM depression

Dacarbazine(DTIC):

Dacarbazine (DTIC) Methylating DNA Malignant melanoma, Hodgkin’s disease Neuropathy,myelosuppression

Temozolamide:

Temozolamide Drug of choice for glioma

Procarbazine:

Procarbazine Methylates and depolymerizes DNA Chromosomal damage Weak MAO i Disulfiram like reaction Mutagenic and carcinogenic

***Cisplatin***:

*** Cisplatin *** Hydrolysed intracellularly Cross linkage of DNA -N7-React with guanine residue and -SH groups of cytoplasmic and nuclear proteins Metastatic testicular and ovarian cancer Solid tumors- lung,bladder,esophageal,gastric,hepatic,head and neck carcinomas

Adverse effects:

Adverse effects Highly emetic Dose dependent renal impairment -Maintain good hydration Tinnitus, deafness, sensory neuropathy and hyperuricemia IV infusion-shock like state

Carboplatin:

Carboplatin Less reactive 2 nd generation-better tolerated Ovarian cacinoma of epithelial origin, squamous carcinoma of head and neck, small lung cell cancer,breast cancer,seminoma Dose limiting toxicity-Thrombocytopenia Less emetogenic

Oxaliplatin:

Oxaliplatin 3 rd generation Target different biomolecules and has activity against cisplatin resistant tumors Use-Colorectal cancer,pancreatic cancer,gastroesophageal cancer Dose limiting-peripheral neuropathy

****Antimetabolites****:

**** Antimetabolites **** Analogues-DNA Components/Coenzymes in nucleic acid synthesis Inhibit utilisation of normal substrate/get incorporated forming dysfunctional molecules CCS-??? Which phase

Slide 55:

Folate antagoninst Purine antagonist Pyrimidine antagonist

***Methotrexate***:

*** Methotrexate *** Folic acid analogue-S phase Oldest, highly efficacious Utilizes folate carrier-----Active polyglutamate ---Inhibits DHF reductase ----inhibits THFA-----inhibits 1 carbon transfer---- purine synthesis Also inhibit thymidylate synthase Curative- choriocarcinoma Maintain remission in acute leukemia NHL, Breast, Bladder, Head and neck, Osteogenic

Slide 58:

Immunosuppressant-Rheumatoid arthritis, psoriasis ADR Bone marrow toxicity- Megaloblastic anemia, pancytopenia Mucositis,diarrhoea **** Folinic acid/ Citrovorum factor/N5 formyl THFA-rapidly reverses Thymidilate also counteracts

Pemetrexed:

Pemetrexed New congener of Methotrexate Target- Thymidylate synthase Like methotrexate utilizes folate carrier-transforms to polyglutamates Adverse effects- Mucositis,Diarrhoea,Myelosuppression Hand foot syndrome Dexamethasone pretreatment, Folic acid and Vitamin B 12 treatment

Purine antagonists:

Purine antagonists Inhibit converison of IMP to adenine and guanine nucleotides Feedback inhibition of purine synthesis Incorporated into dysfunctional DNA and RNA Uses-childhood acute leukemia, choriocarcinoma

Azathioprine:

Azathioprine Converted to 6-MP Immunosuppressant action-suppress CMI Rheumatoid arthritis, Ulcerative colitis, Organ transplantation

Slide 62:

Dose reduced to 1/2 -1/4 Genetic deficiency Xanthine oxidase Mucositis,gut damage

Slide 63:

6 thioguanine -not substrate for xanthine oxidase -s- methylation ? allopurinol dose reduction

Adverse effects:

Adverse effects Hyperuricemia Delayed myelosuppression

Fludarabine:

Fludarabine Newer Phosphorylated - triphosphate -incorporated to form dysfunctional DNA, interferes with DNA repair CLL,NHL Myelosuppression,opportunistic infection, myalgia , arthralgia

Pyrimidine antagonist:

Pyrimidine antagonist Antineoplastic , antifungal, antipsoariatic 5-Fluorouracil Capecitabine Cytarabine

5-Fluorouracil:

5-Fluorouracil Inhibit thymidylate synthase Selective failure of DNA synthesis Thymidine can partially reverse 5-FU toxicity Leucovorin enhances efficacy Colon,rectum,stomach,pancreas,liver ,urinary bladder,head and neck Metabolised by DPD- deficiency---toxicity Hand foot syndrome,myelosuppression,mucositis

Capecitabine:

Capecitabine Orally active prodrug of 5-FU Metastatic colorectal cancer 2 nd line metastatic breast cancer along with taxanes Hand foot syndrome and diarrhoea

Cytarabine(Cytosine arabinoside):

Cytarabine (Cytosine arabinoside ) Inhibits DNA synthesis-Inhibitor of DNA polymerase DNA repair is also affected CCS-S phase Useful in leukemias and lymphomas AML, lymphoblastic leukemia, blast crisis in CML,NHL Bone marrow suppression

Microtubule damaging agents:

Microtubule damaging agents Vinca alkaloids- Vincristine,Vinblastine,Vinorelbine Taxanes-Paclitaxel,Docetaxel Estramustine-estradiol+normustine

***Vinca alkaloids***:

*** Vinca alkaloids*** Periwinkle- Vinca rosea CCS-M phase Mitotic inhibitor Binds to tubulin -prevents polymerization- assembly of microtubules Chromosome fail to move apart Metaphase arrest

Vincristine:

Vincristine Use-Remission of ALL AML, HL, Wilm’s tumor, Ewing’s sarcoma, neuroblastoma , Carcinoma lung ADR-Peripheral neuropathy , alopecia Ataxaia,autonomic dysfunction,nerve palsies SIADH

Vinblastine:

Vinblastine Use-Hodgkin’s disease,Kaposi sarcoma,breast testicular cancer ADR- Myelosuppression vin B lastine - B one Marrow Suppression SIADH,Local tissue necrosis

Vinorelbine:

Vinorelbine Newer semisynthetic vinblastine analogue Use-non small cell lung cancer ADR- vi N orelbine- N eutropenia

Taxanes:

Taxanes Western Yew tree Binds to beta tubulin Enhance polymerisation Microtubules are stabilised Depolymerisation is prevented Abnormal arrays

Slide 77:

Use-Metastatic ovarian and breast carcinoma Toxicity Reversible myelosuppression Stocking and glove neuropathy Acute anaphylactoid reactions Cremophor Pretreatment with dexamethasone and antihistamines Less with albumin bound paclitaxel

Docetaxel:

Docetaxel Effective in refractory breast and ovarian cancer Toxicity- Neutropenia Polysorbate -so less hypersensitivity

Estramustine:

Estramustine Estradiol + normustine Binds to beta tubulin -Interferes with organisation into microtubules Use-advanced or metastatic prostate cancer non responsive to hormones Myelosuppression , estrogenic ADR

Topoisomerase inhibitors:

Topoisomerase inhibitors Topoisomerase 1 inhibitors- I rinotecan,Topotecan Topoisomerase 2 inhibitors- Eto poside,Teneposide

Topoisomerase 1 inhibitors:

Topoisomerase 1 inhibitors Camptothecins CCS-S phase Topotecan,Irinotecan Prevents reasealing of nicks produced by Topoisomerase 1

Slide 83:

Topotecan metastatic ovarian and small cell lung cancer Bone marrow depression- neutropenia Irinotecan-prodrug - to-SN-38 Metastatic or advanced colorectal cancer Combined with 5 FU and leucovorin Toxicity- Diarrhoea,neutropenoa

Topoisomerase 2 inhibitors:

Topoisomerase 2 inhibitors Epipodophyllotoxin Arrest cell in G2 Cause persistent cleavage in the double stranded DNA-prevents resealing Testicular tumor,Ca lung Toxicity- alopecia,leucopenia

Antitumor antibiotics:

Antitumor antibiotics Intercalate between DNA strands and interfere with its template function Actinomycin D Single strand breaks Wilms tumor Rhabdomyosarcoma Vomiting Stomatitis desquamation Daunorubicin Doxorubicin Anthracycline Block DNA and RNA syntheis Activate topoisomerase 2 Generate free radicals AML,ALL Solid tumors CARDIOTOXICITY 2-3 days-ECG changes arrhythmias Hypotension,CHF Red urine,extravastion Epirubicin Newer anthracycline Adjuvant Ca breast Alopecia Hyperpigmentation Dose - cardiotoxicity

Slide 87:

Mitoxantrone No quinone type free radicals AML Refractory Ca prostate Bone marrow depression Mucosal inflammation Bleomycin Mixture- glycopeptide Ab Chelate Cu and Fe Superoxide ions-chain scission,inhibit repair Testicular tumor Squamous cell CA Intrapleural /Peritoneal inj -↓ fluid collection Pulmonary fibrosis Mucocutaneous Toxicity Mitomycin C Like alkylating agent-crosslink Free radicals Superficial bladder- intravesical instlln Resistant Ca stomach,cervix,colon Myelosuppression HUS

Miscellaneous:

Hydroxyurea Block conv of ribonucleotide to deoxy ribonucleotide ---S Phase CML,psoriasis Polycythemia vera Radiosensitiser First-sickle cell disease Myelosuppression *************L- Asparaginase L- ASPase Peg- asparginase ************* Leukemic cells are deficient in L asparagine synthase Depend on medium for L- aspargine L- ASPase degrade L- Asparagine -L-Aspartic acid Cell death Induction of remission ALL Resistance Neutralizing Antibodies Toxicity Hyperglycemia, raised TG, pancreatitis, liver damage Allergy Miscellaneous

Slide 89:

Tretinoin Form of Vitamin A Prevents PML-RAR dimer Degrades PML-RAR fusion Acute promyelocytic (APL) Along with anthracycline Retinoic acid syndrome Dryness of skin eye,nose,mouth,pruritus , epistaxis Arsenic Trioxide Reactive oxygen free radicals APL Nausea,vomiting,sensory disturbances Thalidomide suppressing TNF α and by modulating IL-2. counteract cancer associated cachexia retard tumour growth inhibit angiogenesis . Multiple Myeloma ENL Teratogenic-phocomelia

Targeted drugs:

Targeted drugs Selectively kill/inhibit cancer Specific monoclonal antibody Synthetic compounds

Slide 91:

Imatinib Nilotinib Tyrosine pr kinase inhibitor Bcr-Abl PDGF C-Kit CML Dermatofibrosarcoma GIST Abdominal pain Vomiting Urinary retention Gefitinib Erlotinib Epidermal growth factor receptor Non small cell lung cancer Skin rash, diarrhoea Cetuximab Chimeric monoclonal antibody Advanced or metastatic carcinoma of head Acneform skin rash Anaphylactoid reactions

Slide 92:

Bevacizumab Humanised monoclonal antibody that binds to VEGF Metastatic colorectal cancer NSCLC Rise in BP Thromboembolism Sunitinib VEGF-2 receptor inhibitor PDGF receptor Metastatic renal cell carcinoma Hypertension rash Bortezomib Inhibit proteasome NF- κ B is not released Multiple myeloma Peripheral neuropathy MonoclonalAb Unarmed Armed Direct signalling of apoptosis ADCC,CDC Immunotoxin /Radioactive isotopes

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Antibodies Monoclonal Abs Polyclonal Abs Fusion protein

Slide 94:

ANTIBODIES Derived from different B Lymphocytes cell lines POLYCLONAL MONOCLONAL Derived from a single B cell clone Batch to Batch variation affecting Ab reactivity & titre MAb offer Reproducible, Predictable & Potentially inexhaustible supply of Ab with exquisite specificity Enable the development of secure immunoassay systems . NOT Powerful tools for clinical diagnostic tests

Evolution of MAbs:

Evolution of MAbs Murine MAB Chimeric MAB Humanized MAB Human MAB

Murine Antibody:

Murine Antibody Constant region Variable region Cdr  complementarity determining region omab Eg.Tositumomab

Chimeric Mab:

Chimeric Mab Constant region Variable region Cdr  complementarity determining region ximab 30% mouse 70% human Eg . Rituximab Abciximab Infliximab

Humanised Mab:

Humanised Mab Constant region Variable region CDR  Complementarity determining region zumab 90-95% human Eg : Trastuzumab Alemtuzumab Omalizumab

Human Mab:

Human Mab Constant region Variable region Cdr  complementarity determining region mumab Adalimumab

Human MAB :

Human MAB Less immunogenic better penetrance (small size) Higher t½

Types of MAbs:

Types of MAbs Unarmed Armed MAb radioisotopes toxins drugs

Naked MAbs /Unarmed :

Naked MAbs /Unarmed no attached drug or radioactive material mark the cancer cells  for the immune system to destroy it or attach to receptors  to prevent binding of growth factors eg : a) Trastuzumab b) Rituximab c) Bevacizumab d) Alemtuzumab

Conjugated MAbs:

Conjugated MAbs Tagged, labeled or loaded Attached to Radionuclides (Radio immunotherapy)-Ibritumomab-Y90, Tositumab-I-131 Toxins ( Immunotoxins )- Ozogamicin,Gemtuzumab

RITUXIMAB:

RITUXIMAB Approved -1997 Type - chimeric Target- CD20 B cell antigen Mechanism -ADCC and CDC Indication - B cell lymphomas,NHL,CLL . Toxicity - fever,rash,dyspnea,Bcell depletion,neutropenia

TRASTUZUMAB:

TRASTUZUMAB Indication - metastatic breast cancer Colorectal and NSCL ca Toxicity cardiomyopathy ,infusion related toxicity

Hormonal Drugs:

Tumors that are hormone sensitive 1) hormone responsive , in which the tumor regresses following treatment with a specific hormone 2) hormone dependent , in which removal of a hormonal stimulus causes tumor regression Hormonal Drugs

***Steroids***:

Curative- Lympholytic -childhood leukemia, lymphoma Palliative in Hodgkins Secondary role in hormone responsive Ca breast For controlling complications like hypercalcemia,hemolysis,bleeding,retinoic acid syndrome,increased ICT,mediastinal edema due to radiotherapy Symptomatic relief-mood elevation,antipyretic Antiemetic ***Steroids***

Adverse effects:

can predispose to infection (due to its immunosuppressant action) ulcers and pancreatitis. hyperglycemia, cataract formation glaucoma, osteoporosis change in mood (euphoria or psychosis). Adverse effects

ESTROGENS:

Provide symptomatic relief in carcinoma prostate(androgen dependent tumour ) ESTROGENS

***SERMS***:

Selective estrogen modulators Eg: Tamoxifen ***SERMS***

Selective estrogen down regulators:

first FDA approved agent - Fulvestrant improved safety profile, faster onset longer duration of action than the SERMs due to their pure ER antagonist activity postmenopausal women with hormone receptor-positive metastatic breast cancer Selective estrogen down regulators

AROMATASE INHIBITORS:

Aromatase inhibitors decrease the production of estrogen in these women. AROMATASE INHIBITORS

NON STEROIDAL :

anastrozole , letrozole -- nonsteroidal . 1) more potent 2) more selective than aminoglutethimide , 3) No need to be supplemented with hydrocortisone 4) do not predispose to endometrial cancer 5) devoid of the androgenic side effects NON STEROIDAL

ANTIANDROGEN:

Antagonise androgen action Eg:flutamide,bicalutamide ANTIANDROGEN

5-alpha reductase inhibitor:

Inhibit conversion of testosterone to dihydrotestosterone in prostate Eg: Finasteride,Dutasteride Palliative effect in advanced carcinoma prostate 5-alpha reductase inhibitor

GnRH Agonists:

Inhibit estrogen/androgen secretion by suppressing FSH & LH release from pituitary Palliative effect in advanced estrogen/androgen dependent carcinoma breast/prostate leuprolide and goserelin are analogs of GnRH . GnRH Agonists

PROGESTINS-USES:

Temporary remission in advanced ,recurrent ,metastatic endometrial carcinoma Palliative treatment of metastatic carcinoma breast unresponsiveness to tamoxifen-Megestrol State of well being in cachectic patients PROGESTINS-USES

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