alkylating agents: nitrogen mustards 1)bendamustine 2)cyclophosphamide 3)estramustine 4)ifosfamide...
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Alkylating agents:
Nitrogen Mustards
1)Bendamustine
2)Cyclophosphamide
3)Estramustine
4)Ifosfamide
5)Mechlorethamine
6)Melphalan
Platinum analogs
7)Carboplatin
8)Cisplatin
9)Oxaliplatin
Triazenes
10) Dacarbazine
11) Procarbazine
12) Temozolomide
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Miscellaneous
13) Busulfan
14) Chlorambucil
15) Lomustine
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Alkylating agents
-Transfer alkyl group to cellular elements
-Alkylation of DNA
-Drug – Cyclization – ethyleimonium ion – transfer
alkyl group to DNA
Nitrosoureas
-Carbamoylation of lysine of proteins
-Single strand or both strands – BIFUNCTIONAL
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-DNA Strand breakage
-Cross linking of DNA
-CCNS.
-Mostly in late G1 & S
Pharmacological effects :
- Dose related ADR. On rapidly growing tissue
-Carinogenic – Secondary esp. AML
-VESICANT
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CYCLOPHOSPHAMIDE
NITROSOUREAS:
-Not cross resistant with other alkylating agents
-Enter BBB- lipid soluble – Brain tumors
-Oral administration
-STREPTOZOCIN
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ADR• Acrolein is the metabolite
• Responsible for causing hemorrhagic cystitis– Suprapubic pain– Hematuria– Cyctoscopic findings
• ***This is prevented/treated by MESNA (mercaptoethanesulfonate)
• Rarely cyclophosphamide can cause SIADH and pulmonary toxicity
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NON CLASSICAL ALKYLATING AGENTS:
PROCARBAZINE: Hodgkin's, Non – Hodgkin's, Brain
-Microsomal enzymes – azoprocarbazine + H2O2
-One metabolite – weak MAOI
-Increase risk of secondary cancer
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DACARBAZINE
-Activation in liver monomethyl derivative
diazomethane, methyl Carbonium ion cytotoxic
-Malignant melanoma, HL, Soft tissue sarcomas,
neuroblastoma.
-Potent vesicant
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BENDAMUSTINE:
-Bi functional
PLATINUM ANALOGS: Cisplatin
Carboplatin
Oxatiplatin
-Kill cells in all stage of cell cycle
-Synergism with alkylating agents, fluoropyrimidines &
taxanes.
-vigorous hydration – Renal toxicity.
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-Oxaliplatin + 5-FU + leucovorin – FOLFOX regimen – metastatic colorectal cancer
- Severe nausea & vomiting
Neurotoxicity- dose limiting.
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Antimetabolites
Folic Acid Analogs Purine Analogs Pyrimidine Analogs
Methotrexate Mercaptoguanine Fluorouracil
TrimetrexatePemetrexed
ThioguanineFludarabine PhosphateCladribine
Cytarabine GemcitabineCapecitabine
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Anti metabolites:
Folate antag:-
1)Methotrexate
2)Pemetrexed
Punine analogs:-
3) Cladribine
4) Clofarabine
5) Fludarabine
6) Mercaptopurine
7) Pentostatin
Pyramiding analogs.
8) Azacitidine
9) Capecitabine
10) Cytarabine
11) Decitabine
12) Fluorouracil
13) Gemcitabine
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Antimetabolits: sites of drug action
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Methotrexate (MTX)• MTX is a folic acid analog that binds with high
affinity to the active catalytic site of dihydrofolate reductase (DHFR)
• Thus it interferes with the synthesis of tetrahydrofolate (THF)
• THF serves as the key one-carbon carrier for enzymatic processes involved in de novo synthesis of thymidylate, purine nucleotides, and the amino acids serine and methionine.
• Inhibition of these various metabolic processes thereby interferes with the formation of DNA, RNA, and key cellular proteins.
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Mechanism of Resistance
1. Decreased drug transport
2. Altered DHFR3. Decreased
polyglutamate formation
4. Increased levels of DHFR
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Contd..• Most commonly used anticancer drug. • Cell cycle specific (CCS) drug and acts during S phase
of the cell cycle. • Antineoplastic, immunosuppressant and
antiinflammatory• Used in RA, psoriasis • Well absorbed orally; can also be given IM, IV or
intrathecally**. • It is bound to plasma proteins, does not cross the BBB
and most of the drug is excreted unchanged in urine.• It is a weak acid and so is excreted better at high urine
pH. Appropriate hydration and alkalinizing the urine is important to prevent renal tox with MTX
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Leucovorin Rescue
Mechanism of action of methotrexate and the effect of administration of leucovorin.
• FH2 = dihydrofolate• FH4 = tetrahydrofolate• dTMP = deoxythymidine
monophosphate• dUMP = deoxyuridine mono
phosphate.
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Anti-metabolites:-
1)Methotrexate:- Mechanism of action
Leucovorin rescue
Resistance:-
Uses:- ALL, Choric cancer , Burkitt's, breast cancer,
Head & Neck Cancer
Inflammatory diseases
PR:- Intrathecal – Pharmacological sanctuary
ADR:- Renal damage, Cirrhosis, Pulmonary infiltrates
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2) 6 – MP:- Azathioprine –
6MP PK:- DI MOA Allopurinol
3) 6 – TG – Purine Analog
Acute nonlymhocytic leukemia + daunorubicin + Cytarbine
6 – TG
HGPRT TGMP di & tri PO4
Θ Biosynthesis of Purines Cancer abc admin by allopurinol
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4) Fludarabime:- CLL, hairy cell leukemia, indolent
NHL high doses – encephalopathy, blindness
and death.
5) Hairy cell leukemia, CLL, NHL
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Enzyme inhibitors
Anthracy clines
1) Damorubicin
2) Doxorubicin
3) Epirubicin
4) Idraubicin
5) Mitoxantrone
Topoismerase inhibitors
6) Etoposide
7) Irinotecarn
8) Topotecam
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Anthracy clines
Inhibit topoisornerase
High –affinity binding to DNA through intercalation –
blockade of synthesis of DNA & RNA, & DNA strand
scission
Generation of Seniquinone & O2 free radicals though
Fe dependent process
Binding to cellular membranes to alter fluidity & non
tram sport
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Doxorubicin - Used in Many Cancer
Carditoxi city - Acute
Chronic
DEXRAZOXANE
“ Radiation recall reaction”