cancer chemo 1

7/30/2019 Cancer Chemo 1

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Cancer

Chemotherapy

Firoz anwar.


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100 trillion cell,100billionCell new cells

daily,

mitosis,mutation,apoptosis,mitosis(neoplasma.tumor)contact

inability,supergrowt,invasiveness,mutation,

metastasis,cancer


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Cancer

One type of neoplasm (tumor), which is anabnormal mass of tissue, the growth of cell

exceeds & is uncorordinated with that of normal

tissue & persists in same excessive manner

even after the cessation of the stimuli Two types:

1. Benign tumor:remain localised, cant

spread to other sites

2. Malignant tumor: can invade, destroyadjacent structures and spread to distant

sites


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Pathogenesis

Mutations in genes, involved in mitosis

Oncogenes: stimulate mitosis

Eg. SIS gene

Tumor suppressor genes: inhibit mitosis

Eg.p53 gene

Genes that stimulate angiogenesis


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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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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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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 Action

Alkylate 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

/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

(DECREASE IN WBC)and thrombocytopenia(low

pletelet count)

Cyclophosphamide/Ifosfamide - hemorrhagic

cystitis(inflam bladder)

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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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 the synthesisof precursors of DNA and RNA

To function as a cofactor folate must be

reduced 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 aminoimidazole carboxamide ribonucleotide*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, rheumatoidarthritis, acute lymphoblastic leukemia,

meningeal leukemia,choriocarcinoma(PLACENTA),osteosarcoma, mycosis fungoides,Burkitts(b lymphocy) and non-

Hodgkins lymphomas, cancers of thebreast, head and neck, ovary, andbladder


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Pemetrexed

Therapeutic Uses

Pemetrexed- Mesothelioma(protected

lining covering almost all internal

organs)


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Cladribine

-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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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

Therapeutic Uses Induction of remissions in acute leukemia

Treats meningeal leukemia

Treatment of acute nonlymphocytic

leukemia

In combination with anthracyclines or

mitoxantrone it can treat non-Hodgkinslymphomas


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Gemcitabine

Gemcitabine is S-phase specific

it is a deoxycytidine antimetabolite

it undergoes intracellular conversion to

gemcitabine 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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cancer chemo 1

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