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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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