ANTI- CANCER DRUGS

By- Dr. Sushrut Varun Satpathy

3rd year PG

Deptt. Of Clinical Pharmacology

Moderator-

Dr. Chandrakala Sharma

Assoc. Professor

Clinical pharmacology

SMIMS

Protocol -

1. Origin of cancer chemotherapy2. Introduction 3. Goals of therapy4. Classification 5. General principles of chemotherapy 6. Cell cycle and clinical importance 7. Individual drugs – Alkylating agent- Nitrogen mustards,

triazines, platinum coordination complexes8. Antimetabolites – Mtx, purine analogues, pyrimidine

analogues9. Mitotic spindle inhibitor 10. Anti-tumor antibiotics11. Targeted Drugs12. Hormones and related agents 13. Resistance to anti-cancer drugs

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 1943Luis Goodman and Alfred Gillmen demonstrated it for the first time.

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

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

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

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.

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 - A. Alkylating agents 1. Nitrogen mustards – Mechlorethamine (Mustine HCL),

Cyclophosphamide, Ifosfamide, Melphalan, Chlorambucil 2. Ethylenimine - Thio-TEPA, hexamethylmelamine

(Altretamine)

3. Alkyl sulfonate – Busulfan

4. Nitrosoureas – Carmustine, Lomustine, Streptozocin

5. Triazines - Procarbazine, Dacarbazine, Temozolomide

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

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

8.Miscellaneous – Hydroxyurea, L-Asparaginase, Tretinoin, Arsenic trioxide

B. Targeted Drugs – 1.Tyrosine Protein Kinase Inhibitors – Imatinib,

nilotinib2. EGF receptor inhibitors – Geftinib,

Erlotinib,Cetuximab3. Angiogenesis Inhibitors – Bevacizumab,

Sunitinib4. Proteasome Inhibitor – Bortezomib5. Unarmed monoclonal antibody – Rituximab,

Trastuzumab

C. Hormonal drugs – 1. Glucocorticoids – Prednisolone and others 2. Estrogens – Fosfestrol, Ethinylestradiol3. Selective estrogen receptor modulators-

Tamoxifen,Toremifene4. Selective estrogen receptor down regulators –

Fulvestrant 5. Aromatase Inhibitors – Letrozole, Anastrozole ,

Exemestane6. Antiandrogens – Flutamide,Bicalutamide 7. 5-α reductase Inhibitors – Finasteride,

Dutasteride 8. GnRH analogues –

Nafarelin,Leuprorelin,triptorelin9. GnRH antagonists – Cetorelix, Ganirelix, Abarelix 10. Progestins – Hydroxyprogesterone acetate, etc.

General Principles of Chemotherapy of Cancer1. Analogous with Bacterial chemotherapy – differences are

Selectivity of drugs is limited – because “I may harm you” No or less defence mechanism – Cytokines adjuvant now

2. All malignant cells must be killed to stop progeny – survival time is related to no. of cells that escape Chemo attack

3. Subpopulation cells differ in rate of proliferation and susceptibility to chemotherapy

4. Drug regimens or combined cycle therapy after radiation or surgery (Basis of treatment now in large tumour burdens)

5. Complete remission should be the goal – but already used in maximum tolerated dose – so early treatment with intensive regimens

6. Formerly single drug – now 2-5 drugs in intermittent pulses – Total tumour cell kill – COMBINATION CHEMOTHERAPY

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

• 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

G1 - primary growth phase

S – synthesis; DNA replicated

G2 - secondary growth phase

collectively these 3 stages are called interphase

M - mitosis

C - cytokinesis

21

Daughter Cells

DNA Copied

Cells Mature

Cells prepare for Division

Cell Divides into Identical cells

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 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 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 - 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 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

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

IFOSFAMIDE – Congener of cyclophosphamide Longer and dose dependent T1/2

used in bronchogenic, breast, testicular,bladder ,head and neck carcinomas

Dose limiting toxicity – Haemorrhagic cystitisMesna is a SH- compound -- excreted in urine – binds

and inactivates the vesicotoxic metabolites of ifosfamide and cyclophosphamide

Causes less alopecia and less emetogenic

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

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 PROCARBAZINE –Not a classical alkylating agent, similar propertiesAfter metabolic activation – methylates and

depolymerizes DNA – chromosomal damage Mutagenic and carcinogenic potentialComponent 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 - CISPLATIN – Heavy metal complex , CCNSHydrolysed intracellularly – highly reactive moiety –

cross-linking DNA ( both intrastrand and interstrand) Favored site – N7 of guanine residueAlso reacts with –SH groups of cytoplasmic and nuclear

proteinsEffects resemble – alkylating agent and radiation Plasma protein bound, penetrates tissuesSlowly excreted in urine, T1/2 – 72 hrsHighly effective – testicular, ovarian, endometrial and

bladder CaAlso used in Lung and Oesphageal Ca

Dose – Cisplatin adm. Slow i.v infusion 50-100 mg/m2 BSA every 3-4 weeks

Adverse effects – Most emetogenic anticancer drug, controlled by

5HT3 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 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

1. Folic acid analogue – Mtx, Pemetrexed2. Purine analogue – 6-MP, 6-TG, Fludarabine,

Cytarabine, pentostatin3. Pyrimidine analogue – 5-Fluorouracil ,

Cytarabine (cytosine arabinoside), Capecitabine, Gemcitabine

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 Methotrexate

Dihydrofolate reductaseDihydrofolic acid Tetrahydrofolic acid(DHFA) (DHFR) (THFA)

Leucovorin synthesis of purinesFolinic acid and thymidylate(N5 formyl FH4)

Citrovorum factor DNA and RNA synthesis

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/m2 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 - 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/m2 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

Resistance:

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

Pemetrexed Newer congener of Mtx Primarily targets the enzyme Thymidylate synthaseThough 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/m2 i.v every 3 weeks

Purine analogues - 6-MERCAPTOPURINE and 6-THIOGUANINE – Highly effective anti-neoplastic drugssynthesis 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-TGAzathioprine and 6-MP oxidised by xanthine oxidase

Allopurinol

xanthine oxidase6-Mercaptopurine 6-Thiouric Acid

Dose reduced to 1/4th to 1/2nd if allopurinol is given concurrently

Thioguanine not a substrate for xanthine oxidase – (s-methylation)

Cont…6-MP and 6-TG Methylation by TPMT is an additional pathway

of 6-MP metabolismGenetic 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/m2/d for 5-20 days

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/m2 BSA daily for 5 days every 28 days by i.v infusion

Pyrimidine analogues - FLUOROURACIL (5-FU) –

Mechanism of action -

Fluorouracil FdUMP

Thymidylate synthetase

dUMP TMP

DNA synthesis

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… CYTARABINE (Cytosine arabinoside) – Cytidine analogueSingle most effective agent for induction of remission

in AMLDrug is activated by kinases to AraCTP – inhibitor of

Dna polymerasesOf all antimetabolites – Cytarabine is the most

specific for the S phase of the cell cycleResistance to cytarabine can occur either due to

decreased uptake or decraesed conversion to AraCTP

High dose – Neurotoxicity ( Ataxia and peripheral neuropathy)

Pyrimidine analogues…cont… GEMCITABINE – Deoxy-Cytidine analogue – converted – active

diphosphate and triphopshate nucleotide formGemcitabine diphosphate – inhibits

ribonucleotide reductase – diminish pool of deoxyribonucleoside triphosphates required for DNA synthesis

Can be incorporated into DNA – chain termination

PK- elimination mainly by metabolismClinical 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 - 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 plantCCS agent , act during M phase of the cycleBlock the formation of Mitotic Spindle by preventing

the assembly of tubulin dimers into microtubules

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..

PK- given parenterally, penetrate most tissues except CSF

cleared mainly via biliary secretions

Clinical use – Vincristine - Acute leukemias, lymphomas, Wilm’s Tumor

and NeuroblastomaVinblastine – Lymphomas,Neuroblastomas,Testicular

ca.and Kaposi’s sarcomaVinorelbine – 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…. 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 G2 phase of the cell cycle

Teniposide is an analogue with similar propertiesPK- 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

Etoposide and Teniposide

forms complex with DNA and topoisomerase ІІ

prevent resealing of broken DNA strand

Cell deathToxicity – Etoposide and Teniposide are GI

irritants and cause alopecia and bone marrow suppression

Natural Product Anticancer Drugs –cont….

TOPOTECAN and IRINOTECAN –

Obtained from camptotheca acuminata tree2 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 - 2nd line agent – Advanced Ovarian Ca and for small cell lung Ca.

Irinotecan – Metastatic Colorectal CaToxicity – Myelosuppression and Diarrhoea

Natural Product Anticancer Drugs –cont….

TAXANES – Paclitaxel , docetaxel Derived from the bark of the western yew treePaclitaxel 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 - Made up of several structurally dissimilar

microbial products and includes the anthracyclines, bleomycin and mitomycin

ANTHRACYCLINES – Doxorubicin, daunorubicin, idarubicin,

epirubicin, mitoxantroneIntercalate between base pairs, inhibit

Topoisomerase ІІ , and generate free radicalsBlock synthesis of RNA and DNA – cause DNA

strand scission, membrane disruption also occurs

Anthracyclines CCNS drugs

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…

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… MITOMYCIN-CCCNS , metabolized by liver enzymes – forms an

alkylating agent – crosslinks DNAMitomycin given intravenously and is rapidly

cleared by hepatic metabolismUses- 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 -

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-

First selectively targeted drug to be introducedInhibits 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… 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 - 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…

autophosphorylation 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 (Erbβ1, 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..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 Abs Targeted

againstIndication 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 - GLUCORTICOIDS – Prednisolone - most commonly used glucorticoid in

Ca.chemo. Used for combination chemotherapy in leukemia and lymphomas

ESTROGEN – Physiological antagonists of androgensAntagonizes 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

PROGESTINS –Medroxyprogesterone acetate,

hydroxyprogesterone caproate and megestrol 2nd 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

GnRH agonists - Goserelin, Nafarelin and leuprolide act as agonist of

GnRH used in advanced prostatic caA/e- flaring up of disease, hot

flushes,impotence,gynaecomastia and osteoporosis

GnRH antagonist –Cetrorelix, ganirelix and abarelix are antagonist of GnRHDecrease the release of gonadotropins without causing

initial stimulationCan be used in prostatic ca without the risk of flare up

reaction

AROMATASE Inhibitors – Anastrozole, letrozole etc

Aromatase is the enzyme responsible for conversion of androstenedione ( androgen precursor) to estrone (estrogenic hormone)

1st gen.- aminoglutethimide2nd gen.- formestane, fadrozole,rogletimide3rd gen.- exemestane,letrozole,anastrozole

Aromatase inhibitors – useful in advanced breast ca.

Adverse effects – hot flushes, arthralgia and fatigue

Other anticancer drugs - L- Asparaginase – Enzyme used for treatment of leukemias and

lymphomas- These tumors require exogenous asparagine

for growthL-asparaginase acts by depleting this amino

acid in serumAdm. by IV routea/e – hypersensitivity reactions, acute

pancreatitis and cortical vein thrombosis Pentostatin – Used for treatment of hairy cell leukemiaActs by inhibiting – adenosine deaminase

OCTREOTIDE – Long acting somatostatin analogueUseful 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

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

As2O3 –

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-kB ( involved in cell survival)used – resistant multiple myeloma

Resistance to anticancer drugs - Drug resistance is a major problem in cancer

chemotherapy. Mechanism of resistance includes the following –

1. 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

2. 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

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

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-  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; 7th ed ; 857-877

Katzung’s and Trevor’s, Pharmacology: Examination and board review, Cancer chemotherapy, 10th ed. 465-475

Goodman and Gillman’s 12th ed. Images www.google.com , images

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Chemosensitivity of tumors

► highALLHodgkin’s

diseaseNHLtesticular

cancerSCLCWilms’ tumor

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