Imp Anti Cancers

7/28/2019 Imp Anti Cancers

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Cancer

Chemotherapy


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CELL CYCLE This starts with the cell gearing up for

division by synthesising the componentsnecessary for DNA replication.

G1:Components needed for DNA

synthesis G2:Components needed for mitosis S Phase: DNA synthesis

M Phase: Mitosis for cell division G0, represent a phase in which cell are

not dividing but re-enterthe cycle.

Two checkpoints, one between G1 & Sand one between G2 and M.


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Most anticancer drugs act in S phase, butsome act in M phase and some have

complex actions in the cell cycle. Progress through the cell cycle depends

on the balance between various positive

and negative regulatory forces. The positive forces involve growth factorsthat stimulate the cell to start on the cycleand a series of cyclins and cyclin-

dependent kinases (cdks). The cyclins bind to and regulate the cdks

which in turn control the enzymes of the

cell cycle.


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The D family of cyclins/cdks stimulate the

processes that take the cell through G1 phase.

The D cyclin/cdks complexes plus E/cdkpromotes progression into & through S phase.

Cyclin A/cdk promotes progression through S.

Cyclin B/cdk promotes progression through G2. The action of the cyclin/cdks is modulated by

various negative regulatory forces-proteins that

bind to the cdks and inhibit their action.

These proteins are induced by various genes.

The p53 and Rb which constitute the two

superbreakes on the cell cycle.


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If there is DNA damage, these inhibiors

normally halt the cycle at checkpoint 1,

allowing for repair. If repair fails, apoptosis is initiated.

Cell cycle control is disrupted by:-

1. Abnormal growth factor function

2. Abnormal cyclin/cdks function

3. Abnormal DNA synthesis as a result of

oncogene activity.4. Abnormal decrease in negative regulatory

forces owing to mutation of tumour

suppressor genes.


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GENESIS OF CANCERCELL A normal cell turns into a cancer cell

because of a mutation in its DNA, which

can be inherited or acquired.

Two main categories of genetic changewhich lead to cancer:

1. The inactivation of tumour suppressor genes

2. The activation of proto-oncogenes tooncogenes


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Cell Cycle

Cell Cycle Specific Agents

Antimetabolites

Bleomycin

Podophyllin Alkaloids

Plant Alkaloids

Cell Cycle Non-Specific

Agents

Alkylating Agents

Antibiotics

Cisplatin

Nitrosoureas


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PHASE SPECIFIC DRUGS

CELL CYCLE SPECIFICCELL CYCLE SPECIFIC CELL CYCLE NONCELL CYCLE NON

SPECIFICSPECIFIC

S Phase: CytosineS Phase: Cytosinearabinoside, 6-arabinoside, 6-

MP,MTX,5-FuMP,MTX,5-Fu

Alkylating agentsAlkylating agents

M Phase: Vincristine,M Phase: Vincristine,Vinblastine,Vinblastine,Paclitaxel, Taxol,Paclitaxel, Taxol,

TaxotereTaxotere

AntibioticsAntibiotics

G2 Phase: BleomycinG2 Phase: Bleomycin NitrosoureasNitrosoureas

G1 Phase: 5-FuG1 Phase: 5-Fu Cisplatin,Cisplatin,

ProcarbazineProcarbazine


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Modes of Resistance to Anticancer

DrugsMechanismMechanism Drugs or Drug GroupsDrugs or Drug Groups

Change in sensitivity (orChange in sensitivity (or level)level)

oror binding affinity of targetbinding affinity of target

enzymes or receptorsenzymes or receptors

Etoposide,Etoposide, methotrexate, vincamethotrexate, vinca

alkaloidsalkaloids, estrogen & androgen, estrogen & androgen

receptorsreceptors

Decreased drug accumulation viaDecreased drug accumulation via

expression of glycoprotein expression of glycoproteintransporters, or permeabilitytransporters, or permeability

Methotrexate, alkylating agents,Methotrexate, alkylating agents,

dactinomycindactinomycin

Formation of drug-inactivatingFormation of drug-inactivating

enzymesenzymesPurine & pyrimidine antimetabolitesPurine & pyrimidine antimetabolites

Production of reactive chemicalsProduction of reactive chemicalsthat trap the anticancer drugthat trap the anticancer drug

Alkylators, bleomycin, cisplatin.Alkylators, bleomycin, cisplatin.doxorubicindoxorubicin

Increased nucleic acid repairIncreased nucleic acid repair

mechanismsmechanismsAlkylating agents, cisplatinAlkylating agents, cisplatin

Reduced activation of pro-drugsReduced activation of pro-drugs Purine & pyrimidine antimetabolitesPurine & pyrimidine antimetabolites


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General problems with anticancer

drugs Most of them are antiproliferative, i.e. they

damage DNA and so initiate apoptosis.

They also affect rapidly dividing normalcells.

This leads to toxicity which are usually

severe. To greater or lesser extent the following

toxicities are exhibits by all anticancerdrugs.


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ADR of Antineoplastic Drugs in

Humans


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Distinctive Toxicities of Some Anticancer Drugs

ToxicityToxicity Drug(s)Drug(s)

RenalRenal Cisplatin,* methotrexateCisplatin,* methotrexate

HepaticHepatic 6-MP, busulfan, cyclophosphamide6-MP, busulfan, cyclophosphamide

PulmonaryPulmonary Bleomycin,* busulfan, procarbazineBleomycin,* busulfan, procarbazine

CardiacCardiac Doxorubicin, daunorubicinDoxorubicin, daunorubicin

NeurologicNeurologic Vincristine,* cisplatin, paclitaxelVincristine,* cisplatin, paclitaxel

ImmunosuppressiImmunosuppressi

veve

Cyclophosphamide, cytarabine,Cyclophosphamide, cytarabine,

dactinomycin, methotrexatedactinomycin, methotrexate

OtherOther Cyclophosphamide (hemorrhagicCyclophosphamide (hemorrhagiccystitis);cystitis);procarbazine (leukemia);procarbazine (leukemia);asparaginase* (pancreatitis)asparaginase* (pancreatitis)

*Less Bone marrow suppression marrow sparing*Less Bone marrow suppression marrow sparing

Ch th ti t h t i t


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Proliferating cells are

especially sensitive tochemotherapybecause cytotoxicdrugs usually act bydisrupting DNA

synthesis or mitosis,cellular activities thatonly proliferating cellscarry out.

Unfortunately, toxicityto the anticanceragents is to anyrapidly dividing cells.(e.g. bone marrow,hair follicles, spermforming cells).

Chemotherapeutic agents are much more toxic totissues that have a high growth fraction than to tissuesthat have a low growth fraction.


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Prevention or Management of Drug

Induced toxicities The toxicities of some anticancer drugs

can be well anticipated and hence be

prevented by giving proper medications E.g. mesna is given to prevent

hemorrhagic cystitis by cyclophosphamide

Dexrazoxane, is used to reduce the risk ofanthracycline-induced cardiomyopathy


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Anti-cancer drugs


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Resistance to Cytotoxic Drugs

Increased expression ofMDR-1 gene for a cell

surface glycoprotein, P-glycoprotein

MDR-1 gene is involved with drug efflux

Drugs that reverse multidrug resistance include

verapamil, quinidine, and cyclosporine

MDR increases resistance to natural drug productsincluding the anthracyclines, vincaalkaloids, and

epipodophyllotoxins


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Schematic of P-glycoprotein


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CLASSIFICATIONI. ALKYLATING AGENTS

A. Nitrogen Mustards

1.1. MechlorethamineMechlorethamine

2.2. CyclophosphamideCyclophosphamide

3.3. ChlorambucilChlorambucil

4.4. MelphalanMelphalan

5.5. IfosfamideIfosfamide

B.Alkyl Sulfonates

1.1. BusulfanBusulfan

C. Nitrosoureas

1.1. Carmustine (BCNU)Carmustine (BCNU)

2.2. Lomustine (CCNU)Lomustine (CCNU)


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3.3. SemustineSemustine

4.4. StreptozocinStreptozocin

D. Ethylenimines

1.1. ThiotepaThiotepa

D. Triazenes

1.1. DacarbazineDacarbazine

II. ANTI-METABOLITE

A. Folate Antagonist

1.1. MethotrexateMethotrexate

B. Purine Analogues

1.1. Thioguanine (6-TG)Thioguanine (6-TG)

2.2. Mercaptopurine (6-MP)Mercaptopurine (6-MP)

3.3. FludarabineFludarabine


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C. Pyrimidine Analogues1.1. CytarabineCytarabine

2.2.Fluorouracil (5-FU)Fluorouracil (5-FU)

III. ANTI-BIOTICS

A. Anthracyclines

1.1. DoxorubicinDoxorubicin

2.2. DaunorubicinDaunorubicin

3.3. IdarubicinIdarubicin

B. Bleomycins

C. MitomycinD. Dactinomycin

E. Plicamycin


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IV. PLANT-DERIVED PRODUCTS

A. Vinca Alkaloids

1.1. VincristineVincristine2.2. VinblastineVinblastine

B. Epipodophyllotoxins

1.1. EtoposideEtoposide

2.2. TeniposideTeniposide

C. Taxanes

1.1. PaclitaxelPaclitaxel

IV. ENZYMESA. L-Asparaginase


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VI. HORMONAL AGENTS

A. Glucocorticoids

B. Estrogens/Anti-estrogen1.1. TamoxifenTamoxifen

2.2. Estramustine phosphateEstramustine phosphate

C.Androgens/Anti-androgens

1.1. FlutamideFlutamide

D. Progestins

E. LH-RH Antagonist

1.1. BuserelinBuserelin

2.2. LueprolideLueprolide

F. Octreotide acetate


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VII. MISCELLANEOUS AGENTSA. Hydroxyurea

B. ProcarbazineC. Mitotane

D. Cisplatin

E. Carboplatin

F. Mitoxantrione

VII. MONOCLONAL ANTI-BODIES

VIII. IMMUNOMODULATING AGENTS

A. Levamisole

B. Interferons

1.1. Interferon alfa-2aInterferon alfa-2a

2.2.

Interferon alfa-2bInterferon alfa-2b


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C. Interleukins

1.1. AldesleukinAldesleukin

X. CELLULAR GROWTH FACTORSA. Filgrastim (G-CSF)

B. Lenograstim

C. Sargramostim (GM-CSF)


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Mechanisms & Actions of Useful

Chemotherapeutic Drugs in Neoplastic

Disease


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Alkylating Agents

Nitrogen Mustards Ethylenimines NitrosoureasAlkyl Sulfonates

Cyclophosphamide Thiotepa Busulfan Carmustine

Legend

Drug Class

Sub-class

Prototype Drug


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Alkylating Agents

Mechanism of ActionAlkylate within DNA at the N7 position of

guanine

Resulting in miscoding through abnormalbase-pairing with thymine or in

depurination by excision of guanine

residues, leading to strand breakage Cross-linking of DNA and ring cleavage

may also occur


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Alkylating Agents

Mechanism of Action


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Nitrogen Mustards

Cyclophosphamide

Ifosfamide

Mechlorethamine

Melphalan

Chlorambucil


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Cyclophosphamide Metabolism


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Nitrosoureas

Carmustine

Lomustine

Semustine

Streptozocin-naturally occuring sugar

containing

M.O.A.-cross-link through alkylation of DNA

All cross the blood brain barrier


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Alkylating-Related Agents

Procarbazine

Dacarbazine

Altretamine

Cisplatin

Carboplatin


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Platinum Coordination

Complexes

These compounds alkylate N7 of guanine. They cause nephro- and ototoxicity.

To counteract the effects of nephrotoxicity, give mannitol as an osmotic diuretic,

or induce chloride diuresis with 0.1% NaCl.


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Alkylating Agents

Toxicity Bone marrow depression, with leukopenia and

thrombocytopenia

Cyclophosphamide/Ifosfamide - hemorrhagic

cystitis Reduced by coadministration with MESNA

Cisplatin/Carboplatin- ototoxic and nephrotoxic Nephrotoxicity reduced by chloride diuresis and hydration


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Alkylating Agents

Therapeutic Uses Used to treat a wide variety of hematologic and

solid tumors

Thiotepa ovarian cancer Busulfan chronic myeloid leukemia

Nitrosoureas - brain tumors

Streptozocin insulin-secreting islet cellcarcinoma of the pancreas


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Antimetabolites

Folic Acid Analogs Purine Analogs Pyrimidine Analogs

Methotrexate Mercaptoguanine Fluorouracil

Legend

Drug Class

Sub-class

Prototype Drug


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Folic Acid Analogs

Methotrexate

Trimetrexate

Pemetrexed


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Folate

An essential dietary factor, from which

THF cofactors are formed which

provide single carbon groups for thesynthesis of precursors of DNA and

RNA

To function as a cofactor folate must bereduced by DHFR to THF


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Methotrexate

Mechanism of Action The enzyme DHFR is the 1 site of action

MTX prevents the formation of THF, causing

an intracellular deficiency of folatecoenzymes and accumulation of the toxic

inhibitory substrate, DHF polyglutamate

The one carbon transfer reactions for purineand thymidylate synthesis cease,

interrupting DNA and RNA synthesis


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Major Enzymatic Reactions Requiring Folates as

Substrates*

GARGAR transformylase

AICAR IMPAMP

GMP

AICAR transformylase

10-formylTHF

Formate+

THF

(3)

DHFb

e

5,10-CH2THF 5-CH3THFc

Methionine

Homocysteine

d

(2)

dUMP

dTMP

DNAa

(1)

a,thymidylate synthase; b, dihydrofolate reductase; c, methylenetetrahydrofolate reductase;

d, methionine synthase; e, serine hydroxymethyl transferase*from Bowen


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Resistance


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Methotrexate

Mechanism of Resistance1. Decreased drug transport

2. Altered DHFR

3. Decreased polyglutamate formation

4. Increased levels of DHFR


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Methotrexate

Therapeutic Uses Methotrexate- psoriasis, rheumatoid

arthritis, acute lymphoblastic leukemia,

meningeal leukemia, choriocarcinoma,osteosarcoma, mycosis fungoides,

Burkitts and non-Hodgkins

lymphomas, cancers of the breast,head and neck, ovary, and bladder


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Trimetrexate

Therapeutic Uses

Trimetrexate- Pneumocystis carinii

pneumonia, metastatic colorectal

carcinoma, head and neck carcinoma,pancreatic carcinoma, non-small cell

carcinoma of the lung


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Pemetrexed

Therapeutic Uses

Pemetrexed- Mesothelioma


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Methotrexate

Toxicity Bone marrow suppression

Rescue with leucovorin (folinic acid)

Nephrotoxicgive sodium bicarbonate to alkalinize the

urine


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Purine Antagonists

Mercaptopurine

Thioguanine

Fludarabine Phosphate

Cladribine


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Mercaptopurine/Thioguanine

Must metabolized by HGPRT to the

nucleotide form This form inhibits numerous enzymes of

purine nucleotide interconversion


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Fludarabine Phosphate

M.O.A.- phosphorylated intracellularly by

deoxycytidine kinase to the triphosphate

form The metabolite inhibits DNA polymerase-

and ribonucleotide reductase

Induces apoptosis Tx- non-Hodgkins lymphoma and chronic

lymphocytic leukemia


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Cladribine

M.O.A. -phosphorylated by deoxycytidine

kinase and is incorporated into DNA

Causes DNA strand breaks Tx- hairy cell leukemia, chronic

lymphocytic leukemia, and non-Hodgkins

lymphoma


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Pyrimidine Antagonists

Fluorouracil - S-phase

Cytarabine

Gemcitabine

Capecitabine


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Figure 2. This figure illustrates the effects of MTX and 5-FU on the

biochemical pathway for reduced folates.

X

X5-FU

MTX


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Mechanism of Action 5-FU 5-FU inhibits thymidylate synthase

therefore causing depletion of

Thymidylate

5-FU is incorporated into DNA

5-FU inhibits RNA processing


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Activation of 5-FU


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Therapeutic Uses of 5-FU

Metastatic carcinomas of the breast and

the GI tract

hepatoma carcinomas of the ovary, cervix, urinary

bladder, prostate, pancreas, and

oropharyngeal areas Combined with levamisole for Tx of colon

cancer


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Cytarabine

It is activated to 5 monophosphate(AraCMP) by deoxycytidine kinase

Through a series of reactions it forms

the diphosphate (AraCDP) andtriphosphate (AraCTP) nucleotides

Accumulation of AraCTP potently

inhibits DNA synthesis Inhibition of DNA synthesis is due to

competitive (-) of polymerases and

interference of chain elongation


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Cytarabine

It is a potent inducer of tumor cell

differentiation

Fragmentation of DNA and evidence ofapoptosis is noticed in treated cells

AraC is cell-cycle specific agent, it kills

cells in the S-phase


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Cytarabine

Mechanisms of Resistance deficiency of deoxycytidine kinase

increased CTP synthase activity

increased cytidine deaminase activity

decreased affinity of DNA polymerase for

AraCTP

decrease ability of the cell to transport

AraC


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Cytarabine

Therapeutic Uses Induction of remissions in acute leukemia

Treats meningeal leukemia

Treatment of acute nonlymphocyticleukemia

In combination with anthracyclines or

mitoxantrone it can treat non-Hodgkinslymphomas


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Cytarabine

Toxicities Nausea

acute myelosuppression

stomatitis

alopecia


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Gemcitabine

Gemcitabine is S-phase specific

it is a deoxycytidine antimetabolite

it undergoes intracellular conversion togemcitabine monophosphate via the

enzyme deoxycytidine kinase

it is subsequently phosphorylated togemcitabine diphosphate and gemcitabine

triphosphate


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Gemcitabine

Gemcitabine triphosphate competes with

deoxycytidine triphosphate (dCTP) for

incorporation into DNA strands do to an addition of a base pair before

DNA polymerase is stopped, Gemcitabine

inhibits both DNA replication and repair Gemcitabine-induced cell death has

characteristics of apoptosis


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Gemcitabine

Therapeutic Uses Gemcitabine treats a variety of solid

tumors

very effective in the treatment ofpancreatic cancer

small cell lung cancer

carcinoma of the bladder, breast, kidney,ovary, and head and neck


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Plant Alkaloids

Vinca Alkaloids Podophyllotoxins Camptothecins Taxanes

Vinblastine Etoposide Topotecan Paclitaxel


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Vinca Alkaloids

Vinblastine

Vincristine

Vinorelbine


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Vinca Alkaloids

3

3

Inhibit microtubules

(spindle), causing

metaphase cell arrest

in M phase.


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Vinca Alkaloids

Mechanism of Action

Binds to the microtubular protein tubulin in a

dimeric form

The drug-tubulin complex adds to the formingend of the microtubules to terminate assembly

Depolymerization of the microtubules occurs

Resulting in mitotic arrest at metaphase,

dissolution of the mitotic spindle, and

interference with chromosome segregation

CCS agents- M phase


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Vinblastine

Toxicity Nausea

Vomiting

Marrow depression

Alopecia


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Vinblastine

Therapeutic Uses

Systemic Hodgkins disease

Lymphomas


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Vincristine

Toxicity Muscle weakness

Peripheral neuritis


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Vincristine

Therapeutic Uses

With prednisone for remission of Acute

Leukemia


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Vinorelbine

Toxicity

Granulocytopenia

Therapeutic Uses

non-small cell lung cancer


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Podophyllotoxins

Etoposide (VP-16) Teniposide (VM-26)

Semi-synthetic derivatives of podophyllotoxin extracted

from the root of the mayapple


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Podophyllotoxins

Mechanism of Action

Blocks cells in the late S-G2phase of the

cell cycle through inhibition of

topoisomerase II Resulting in DNA damage through strand

breakage induced by the formation of a

ternary complex of drug, DNA, andenzyme


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Podophyllotoxins

Toxicity Nausea

Vomiting

Alopecia Hematopoietic and lymphoid toxicity


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Podophyllotoxins

Therapeutic Uses

Monocytic Leukemia

Testicular cancer

Oat cell carcinoma of the lung


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Camptothecins

Topotecan

Irinotecan


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Camptothecins

Mechanism of Action

Interfere with the activity ofTopoisomerase I

Resulting in DNA damage

Irinotecan-a prodrug that is metabolized to

an active Top I inhibitor, SN-38

C


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Camptothecins

Toxicity

TopotecanNeutropenia, thrombocytopenia, anemia

IrinotecanSevere diarrhea, myelosuppression

C t th i


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Camptothecins

Therapeutic Uses

Topotecan- metastatic ovarian cancer

(cisplatin-resistant)

Irinotecan- colon and rectal cancer


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Taxanes

Paclitaxel (Taxol)

Docetaxel

Alkaloid esters derived from the Western

and European Yew

T


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Taxanes

Mechanism of Action

Mitotic spindle poison through the

enhancement of tubulin polymerization

T


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Taxanes

Toxicity

PaclitaxelNeutropenia, thrombocytopenia

Peripheral neuropathy Docetaxel

Bone marrow suppression

NeurotoxicityFluid retention

T


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Taxanes

Therapeutic Uses

Paclitaxel- ovarian and advanced breast

cancer Docetaxel- advanced breast cancer


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Antibiotics

Anthracyclines- Doxorubicin &

Daunorubicin

Dactinomycin Plicamycin

Mitomycin

Bleomycin


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Anthracyclines

Doxorubicin

Daunorubicin

A th li


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Anthracyclines

Mechanism of Action

High-affinity binding to DNA through

intercalation, resulting in blockade of DNA

and RNA synthesis DNA strand scission via effects on Top II

Binding to membranes altering fluidity

Generation of the semiquinone free radicaland oxygen radicals

A th li


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Anthracyclines

Toxicity

Bone marrow depression

Total alopecia Cardiac toxicity

A th li


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Anthracyclines

Therapeutic Uses

Doxorubicin- carcinomas of the breast,

endometrium, ovary, testicle, thyroid, and

lung, Ewings sarcoma, and osteosarcoma

Daunorubicin- acute leukemia

Dactinomycin


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DactinomycinMechanism of Action

Binds to double stranded DNA through

intercalation between adjacent guanine-

cytosine base pairs

Inhibits all forms of DNA-dependent RNA

synthesis

Dactinomycin


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Dactinomycin

Toxicity

Bone marrow depression

Oral ulcers

Skin eruptions Immunosuppression

Dactinomycin


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Dactinomycin

Therapeutic Uses

Wilms tumors

Gestational choriocarinoma with MTX

Plicamycin


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PlicamycinMechanism of Action

Binds to DNA through an antibiotic-Mg2+

complex

This interaction interrupts DNA-directed

RNA synthesis

Plicamycin


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PlicamycinToxicity

Hypocalcemia

Bleeding disorders

Liver toxicity

Plicamycin


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PlicamycinTherapeutic Uses

Testicular cancer

Hypercalcemia

Mitomycin


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Mitomycin Mechanism of Action

Bioreductive alkylating agent that

undergoes metabolic reductive activation

through an enzyme-mediated reduction togenerate an alkylating agent that cross-

links DNA

Mitomycin


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MitomycinToxicity

Severe myelosuppression

Renal toxicity Interstitial pneumonitis

Mitomycin


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MitomycinTherapeutic Uses

Squamous cell carcinoma of the cervix

Adenocarcinomas of the stomach,pancreas, and lung

2nd line in metastatic colon cancer


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Bleomycin

Acts through binding to DNA, which

results in single and double strand breaks

following free radical formation andinhibition of DNA synthesis

The DNA fragmentation is due to oxidation

of a DNA-bleomycin-Fe(II) complex andleads to chromosomal aberrations

CCS drug that causes accumulation of

cells in G2

Bleomycin


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BleomycinToxicity

Lethal anaphylactoid reactions

Blistering Pulmonary fibrosis

Bleomycin


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BleomycinTherapeutic Uses

Testicular cancer

Squamous cell carcinomas of the head

and neck, cervix, skin, penis, and rectum

Lymphomas

Intracavitary therapy in ovarian and breast

cancers


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Hormones

Estrogens:

Estrogens inhibit the effects of endogenous

androgens and androgen-dependent metastaticprostatic carcinoma. Diethylstilbestrol is usually

the agent of choice.

Cardiac and cerebrovascular complications and

carcinoma of the male breast are potential adverse

effects.


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Hormones

Several types of hormone-dependent cancer(especially breast, prostate, and endometrialcancer) respond to treatment with their

corresponding hormone antagonists. Estrogen antagonists are primarily used in the

treatment of breast cancer, whereas androgenantagonists are used in the treatment of prostate

cancer. Corticosteroids are particularly useful intreating lymphocytic leukemias and lymphomas.


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Hormones

Progenstins:

Progestins are useful in the management of

endometrial carcinoma and back-up therapy formetastatic hormone-dependent breast cancer.


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Hormones

Antiestrogen: Tamoxifen Tamoxifen is the drug of choice in postmenopausal

women with or recovering from metastatic breast

cancer. It is most effective in patients who haveestrogen receptor-positive tumors.

Tamoxifen is also used as adjunvctive therapy tooophorectomy to leuprolide or goserelin in

premenopausal women with estrogen receptor-positive tumors.


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Hormones

Androgens: Androgen activity in breast cancer is similar to

that of estrogens, perhaps for the same

mechanistic reasons. Virilizing effects and hepatic toxicity make them

unacceptable to most patients. Fluoxymesterone is the most widely used agent. Danazol has use in hematology in aplastic anemia

and congenital anemias.


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Hormones

Glucocorticoids: They are integral components of curative therapy

for acute lymphoblastic leukemia, non-Hodgkinslymphoma, and Hodgkins disease.

Glucocorticoids have essential roles in theprevention of allergic reaction, emesis control,

relief of intracranial hypertension or spinal cordcompression in neurologic complications, and painrelief.


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Hormonal Agents

Estrogen & Androgen

Inhibitors

Gonadotropin-Releasing

Hormone AgonistsAromatase Inhibitors

Tamoxifen Leuprolide Aminogluthethimide

Legend

Drug Class

Sub-class

Prototype Drug


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Anti-Estrogens

Tamoxifen (SERMs)

Raloxifene (SERMs)

Faslodex

Tamoxifen


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Selective estrogen receptor modulator (SERM), have both

estrogenic and antiestrogenic effects on various tissues Binds to estrogen receptors (ER) and induces conformational

changes in the receptor Has antiestrogenic effects on breast tissue. The ability to produce both estrogenic and antiestrogenic

affects is most likely due to the interaction with othercoactivators or corepressors in the tissue and the binding withdifferent estrogen receptors, ER and ER

Subsequent to tamoxifen ER binding, the expression of

estrogen dependent genes is blocked or altered Resulting in decreased estrogen response. Most of tamoxifens affects occur in the G1 phase of the cell

cycle

Tamoxifen


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TamoxifenToxicity

Hot flashes

Fluid retention

nausea

Tamoxifen


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TamoxifenTherapeutic Uses

Tamoxifen can be used as primary therapy formetastatic breast cancer in both men andpostmenopausal women

Patients with estrogen-receptor (ER) positivetumors are more likely to respond to tamoxifentherapy, while the use of tamoxifen in womenwith ER negative tumors is still investigational

When used prophylatically, tamoxifen has beenshown to decrease the incidence of breastcancer in women who are at high risk for

developing the disease

A i A d


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Anti-Androgen

FlutamideAntagonizes androgenic effects

approved for the treatment of prostate cancer

Gonadotropoin-Releasing Hormone


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Gonadotropoin Releasing Hormone

Agonists

Leuprolide

Goserelin



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g

Agonist

Mechanism of Action

Agents act as GnRH agonist, with

paradoxic effects on the pituitary

Initially stimulating the release of FSH and

LH, followed by inhibition of the release of

these hormones

Resulting in reduced testicular androgen

synthesis



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Agonist

Toxicity

Gynecomastia

Edema thromboembolism



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Agonist

Therapeutic Uses

Metastatic carcinoma of the prostate

Hormone receptor-positive breast cancer

A t I hibit


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Aromatase Inhibitors

Aminogluthethimide

Anastrozole

Aminogluthethimide


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Aminogluthethimide

Mechanism of Action

Inhibitor of adrenal steroid synthesis at the

first step, conversion ofcholesterol of

pregnenolone Inhibits the extra-adrenal synthesis of

estrone and estradiol

Inhibits the enzyme aromatase thatconverts androstenedione to estrone


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Aminogluthethimide


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og ut et de

Toxicity

Dizziness

Lethargy

Visual blurring Rash

Therapeutic Uses

ER- and PR-positive metastatic breast

cancer

A t l


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Anastrozole

A new selective nonsteroidal inhibitor of

aromatase

Treats advanced estrogen andprogesterone receptor positive breast

cancer that is no longer responsive to

tamoxifen

Mi ll A tiC A t


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Miscellaneous AntiCancer Agents

Asparaginase

Hydroxurea

Mitoxantrone Mitotane

Retinoic Acid Derivatives

Amifostine

A i


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Asparaginase

An enzyme isolated from bacteria Causes catabolic depletion of serum

asparagine to aspartic acid and ammonia

Resulting in reduced blood glutamine levelsand inhibition of protein synthesis

Neoplastic cells require external source of

asparagine Treats childhood acute leukemia Can cause anaphylactic shock

Hydroxyurea


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Hydroxyurea

An analog of urea

Inhibits the enzyme ribonucleotide reductase

Resulting in the depletion ofdeoxynucleoside triphosphate pools

Thereby inhibiting DNA synthesis

S-phase specific agent Treats melanoma and chronic myelogenous

leukemia

Mitoxantrone


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Mitoxantrone

Structure resembles the anthracyclines Binds to DNA to produce strand breakage

Inhibits DNA and RNA synthesis Treats pediatric and adult acute

myelogenous leukemia, non-Hodgkinslymphomas, and breast cancer

Causes cardiac toxicity

Mechanisms & Actions of Useful

Ch th ti D i N l ti


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Chemotherapeutic Drugs in Neoplastic

Disease


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http://www.arqule.com/demo2.aspx

Tyrosine kinases inhibitor tivantinib (ARQ 197), is designed to block the activity of a molecule

known as c-Met that plays multiple key roles in human cancer,including cancer cell growth, survival, angiogenesis, invasion andmetastasis (the spread of cancer from one part of the body toanother). c-Met is inappropriately expressed in almost all types ofhuman cancer, with an established role in tumor development.

Activating mutations of c-Met have been increasingly identified inhuman cancer.

THERAPEUTIC USES


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DURGDURG INDICATIONINDICATIONMechlorethamineMechlorethamine Hodgkin's disease; non-Hodgkin'sHodgkin's disease; non-Hodgkin's

lymphomalymphoma

CyclophosphamideCyclophosphamide

IfosfamideIfosfamide

ALL, CLL, Hodgkin's disease; non-ALL, CLL, Hodgkin's disease; non-Hodgkin's lymphoma; multiple myeloma;Hodgkin's lymphoma; multiple myeloma;neuroblastoma; breast, ovary, lungneuroblastoma; breast, ovary, lung

cancer; Wilms' tumor; cervix, testiscancer; Wilms' tumor; cervix, testis

cancer; soft-tissue sarcomacancer; soft-tissue sarcoma

MelphalanMelphalan Multiple myeloma; breast, ovarian cancerMultiple myeloma; breast, ovarian cancer

ChlorambucilChlorambucil CLL; primary macroglobulinemia;CLL; primary macroglobulinemia;

Hodgkin's disease; non-Hodgkin'sHodgkin's disease; non-Hodgkin'slymphomalymphoma

ThiotepaThiotepa Bladder, breast, ovarian cancerBladder, breast, ovarian cancer

ProcarbazineProcarbazine Hodgkins DiseaseHodgkins Disease

B l hB l h CMLCML


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BusalphanBusalphan CMLCML

CarmustineCarmustine Hodgkin's disease; non-Hodgkin'sHodgkin's disease; non-Hodgkin's

lymphoma; primary brain tumor; melanomalymphoma; primary brain tumor; melanoma

StreptozocinStreptozocin(streptozotocin)(streptozotocin)

Malignant pancreatic insulinoma; malignantMalignant pancreatic insulinoma; malignantcarcinoidcarcinoid

DacarbazineDacarbazine Malignant melanoma; Hodgkin's disease;Malignant melanoma; Hodgkin's disease;soft-tissue sarcomas; glioma; melanomasoft-tissue sarcomas; glioma; melanoma

Cisplatin,Cisplatin,CarboplatinCarboplatin

Testicular, ovarian, bladder, esophageal,Testicular, ovarian, bladder, esophageal,lung, colon cancerlung, colon cancer

MethotrexateMethotrexate Acute lymphocytic leukemia;Acute lymphocytic leukemia;choriocarcinoma; breast, head, neck, andchoriocarcinoma; breast, head, neck, and

lung cancer; osteogenic sarcoma; bladderlung cancer; osteogenic sarcoma; bladdercancercancer

FluorouracilFluorouracil Breast, colon, esophageal, stomach,Breast, colon, esophageal, stomach,pancreas, head and neck; premalignant skinpancreas, head and neck; premalignant skinlesion.lesion.

CytarabineCytarabine AML, ALL, non-Hodgkin's lymphomaAML, ALL, non-Hodgkin's lymphoma

GemcitabineGemcitabine Pancreatic ovarian lung cancerPancreatic ovarian lung cancer


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GemcitabineGemcitabine Pancreatic, ovarian, lung cancerPancreatic, ovarian, lung cancer

VinblastineVinblastine Hodgkin's disease; non-Hodgkin's lymphoma:Hodgkin's disease; non-Hodgkin's lymphoma:

breast, lung, and testis cancerbreast, lung, and testis cancer

VincristineVincristine ALL; neuroblastoma; Wilms' tumor;ALL; neuroblastoma; Wilms' tumor;rhabdomyosarcoma; Hodgkin's disease; non-rhabdomyosarcoma; Hodgkin's disease; non-Hodgkin's lymphomaHodgkin's lymphoma

PaclitexalPaclitexal Ovarian, breast, lung, bladder, head andOvarian, breast, lung, bladder, head andneck cancerneck cancer

EtoposideEtoposide Testis, small-cell lung, and other lung cancer;Testis, small-cell lung, and other lung cancer;breast cancer; Hodgkin's disease; non-breast cancer; Hodgkin's disease; non-Hodgkin's lymphomas; AML; Kaposi'sHodgkin's lymphomas; AML; Kaposi'ssarcomasarcoma

TopotecanTopotecan Ovarian cancer; small-cell lung cancer; colonOvarian cancer; small-cell lung cancer; colonand lung cancerand lung cancer

DactinimycinDactinimycin Choriocarcinoma; Wilms' tumor;Choriocarcinoma; Wilms' tumor;rhabdomyosarcoma; testis; Kaposi's sarcomarhabdomyosarcoma; testis; Kaposi's sarcoma

DaunorubicinDaunorubicin AML, ALLAML, ALL

DoxorubicinDoxorubicin Soft-tissue, osteogenic, and other sarcoma;Soft-tissue, osteogenic, and other sarcoma;Hodgkin's disease; non Hodgkin's lymphoma;Hodgkin's disease; non-Hodgkin's lymphoma;


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Hodgkin s disease; non-Hodgkin s lymphoma;Hodgkin s disease; non-Hodgkin s lymphoma;acute leukemia; breast, genitourinary,acute leukemia; breast, genitourinary,thyroid, lung, stomach cancer;thyroid, lung, stomach cancer;neuroblastoma and other childhood sarcomaneuroblastoma and other childhood sarcoma

BleomycinBleomycin Testis, and cervical cancer; Hodgkin'sTestis, and cervical cancer; Hodgkin'sdisease; non-Hodgkin's lymphomadisease; non-Hodgkin's lymphoma

L-AsparaginaseL-Asparaginase ALLALL

HydroxyureaHydroxyurea CML, Polycythemia vera, essentialCML, Polycythemia vera, essentialthrombocytosisthrombocytosis

ImatinibImatinib(Gleevac)(Gleevac)

CML, gastrointestinal stromal tumors;CML, gastrointestinal stromal tumors;hypereosinophilia syndromehypereosinophilia syndrome

Interferon-alfa,Interferon-alfa,interleukin 2interleukin 2 Hairy cell leukemia; Kaposi's sarcoma;Hairy cell leukemia; Kaposi's sarcoma;melanoma; carcinoid; renal cell; ovary;melanoma; carcinoid; renal cell; ovary;bladder; non-Hodgkin's lymphoma; mycosisbladder; non-Hodgkin's lymphoma; mycosisfungoides; multiple myeloma; CML;fungoides; multiple myeloma; CML;malignant melanomamalignant melanoma

PrednisonePrednisone ALL, CLL, Non-Hodgkins lymphoma,ALL, CLL, Non-Hodgkins lymphoma,


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PrednisonePrednisone ALL, CLL, Non Hodgkin s lymphoma,ALL, CLL, Non Hodgkin s lymphoma,Hodgkins diseaseHodgkins disease

HydroxyprogesHydroxyprogesteroneteronecaproate,caproate,

Endometrial and Breast CancerEndometrial and Breast Cancer

DiethylstilbestrDiethylstilbestrol, ethinylol, ethinyl

estradiolestradiol

Breast and prostate cancerBreast and prostate cancer

TamoxifenTamoxifen Breast CancerBreast Cancer

PHARMACOKINTICS


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DRUGDRUG PHARMACOKINETICPHARMACOKINETICPROPERTIESPROPERTIES

MechlorethamiMechlorethaminene

I/V. life in plasma is > 10mins.I/V. life in plasma is > 10mins.

CyclophosphaCyclophosphamidemide

P/O, I/V, life is 6.5 hrs.P/O, I/V, life is 6.5 hrs.Biotransformed by cyt P450.Biotransformed by cyt P450.

PlatimunPlatimunanalogueanalogue

I/V.Drug distributes to most tissues.I/V.Drug distributes to most tissues.Cleared in unchaged form byCleared in unchaged form bykidney.kidney.

ProcarbazineProcarbazine P/O active & penetrates into mostP/O active & penetrates into mosttissue +CSF.Eliminated via Hep.tissue +CSF.Eliminated via Hep.MetabolismMetabolism

MTXMTX P/O, I/V & IT.good tissueP/O, I/V & IT.good tissuedistribution. Not metabolized.Cldistribution. Not metabolized.Cl

6-MP & 6-TG6-MP & 6-TG Absorb slowly after P/O adm. Low P/OAbsorb slowly after P/O adm. Low P/Obioavailability.6-MP 20% bond to PP.bioavailability.6-MP 20% bond to PP. life 21 min chlid & 47 min adults life 21 min chlid & 47 min adults


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life 21 min chlid & 47 min adults. life 21 min chlid & 47 min adults.

PlantPlantAlkaloidsAlkaloids

Given I/V. Penetrate most tissuesGiven I/V. Penetrate most tissuesexcept CSF. Cleared via biliaryexcept CSF. Cleared via biliaryexcretion.excretion.

EtoposideEtoposide Well absorbed after P/O adm.Well absorbed after P/O adm.Distributes to most tissues. EliminateDistributes to most tissues. Eliminate

via kidney.via kidney.

PaclitaxelPaclitaxel Given I/V. life 6hrs. Metabolized byGiven I/V. life 6hrs. Metabolized byliver. >10% excreted in urine.liver. >10% excreted in urine.

AntibioticsAntibiotics Given I/V. Metabolized by liver.Given I/V. Metabolized by liver.Excreted in bile & urine.Excreted in bile & urine.

BleomycinBleomycin Given I/V, I/M, I/A, I/T, S/C. CrossesGiven I/V, I/M, I/A, I/T, S/C. CrossesBBB poorly. life 3hrs. Excreted inBBB poorly. life 3hrs. Excreted inurineurine

SIDE EFFECTS


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1. Bone Marrow Suppression Decreased WBCs & Platelets count

1. Gastrointestinal Nausea & Vomiting

Anorexia

Alterations in taste perception

Mucositis

Stomatitis, dysphagia, esophagitis

1. Allopecia

2. Phlebitis

3. Nephrotoxicity

4. Hepatotoxicity

7. Cardiotoxicity

8. Pulmonary Toxicity


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y y Hypersensitivity pneumonitis

Allergic interstitial pneumonia

7. Neurotoxicity

8. Reproductive toxicity

Menstural irregularities Premature menopause

Oligospermia

BleomycinBleomycin Pneumonitis, Alopecia, Pulmonary, Nausea,Pneumonitis, Alopecia, Pulmonary, Nausea,VomitingVomiting


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DoxorubicinDoxorubicin BMS, Cardiac (often delayed), Nausea,BMS, Cardiac (often delayed), Nausea,VomitingVomiting

EtoposideEtoposide BMS, AlopeciaBMS, Alopecia

FluorouracilFluorouracil BMS, Oral & GI ulcers, NVD, AlopeciaBMS, Oral & GI ulcers, NVD, Alopecia

MercaptopurineMercaptopurine BMS, Cholestasis, Nausea, vomiting,BMS, Cholestasis, Nausea, vomiting,pancreatitispancreatitis

MthotrexateMthotrexate BMS, Hepatic, NVD, Alopecia, PulmonaryBMS, Hepatic, NVD, Alopecia, Pulmonarydysfunctiondysfunction

PaclitaxelPaclitaxel BMS, PN, Alopecia,BMS, PN, Alopecia,

VincristineVincristine PN, Paralytic ileus, Neurological ToxicityPN, Paralytic ileus, Neurological Toxicity

VinblastineVinblastine BMS, Alopecia, muscle painBMS, Alopecia, muscle pain

TopotecanTopotecan BMS, DiarrheaBMS, Diarrhea

GemcitabinGemcitabin BMS, PulmonaryBMS, Pulmonary

DRUG INTERACTIONS


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1. avoid concomitant use of cytotoxics with clozapine

(increased risk of agranulocytosis).2. cytotoxics reduce absorption of digoxin tablets.

3. cytotoxics possibly reduce absorption of phenytoin.

4. plasma concentration of bortezomib increased by

ketoconazole .5. plasma concentration of imatinib reduced by

carbamazepine avoid concomitant use

6. imatinib possibly increases plasma concentration of

ciclosporin7. plasma concentration of imatinib increased by

ketoconazole

8. imatinib possibly reduces plasma concentration of

levothyroxine (thyroxine).


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9. plasma concentration of imatinib reduced by

oxcarbazepine avoid concomitant use10. plasma concentration of imatinib reduced by

phenytoin avoid concomitant use

11. plasma concentration of imatinib reduced by

rifampicin avoid concomitant use12. imatinib increases plasma concentration of

simvastatin

13. mitotane possibly reduces anticoagulant effect of

coumarins14. manufacturer of mitotane advises avoid concomitant

use of spironolactone (antagonism of effect)

15. plasma concentration of etoposide possibly

increased by ciclosporin (increased risk of toxicity )


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16. etoposide possibly enhances anticoagulant effect of

coumarins17. plasma concentration of etoposide possibly reduced

by phenobarbital

18. plasma concentration of etoposide possibly reduced

by phenytoin19. toxicity of vinblastine increased by erythromycin

avoid concomitant use

20. metabolism of busulfan inhibited by itraconazole

(increased risk of toxicity)21. plasma concentration of busulfan increased by

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