Post on 08-Dec-2014
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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