Transcript Alkylating agents

Alkylating agents:
Nitrogen Mustards
Platinum analogs
1)Bendamustine
7)Carboplatin
2)Cyclophosphamide
8)Cisplatin
9)Oxaliplatin
3)Estramustine
Triazenes
4)Ifosfamide
10) Dacarbazine
5)Mechlorethamine
11) Procarbazine
6)Melphalan
12) Temozolomide
Miscellaneous
13) Busulfan
14) Chlorambucil
15) Lomustine
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
-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
CYCLOPHOSPHAMIDE
NITROSOUREAS:
-Not cross resistant with other alkylating agents
-Enter BBB- lipid soluble – Brain tumors
-Oral administration
-STREPTOZOCIN
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
NON CLASSICAL ALKYLATING AGENTS:
PROCARBAZINE: Hodgkin's, Non – Hodgkin's, Brain
-Microsomal enzymes – azoprocarbazine + H2O2
-One metabolite – weak MAOI
-Increase risk of secondary cancer
DACARBAZINE
-Activation in liver  monomethyl derivative 
diazomethane,  methyl Carbonium ion  cytotoxic
-Malignant melanoma, HL, Soft tissue sarcomas,
neuroblastoma.
-Potent vesicant
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.
-Oxaliplatin + 5-FU + leucovorin – FOLFOX
regimen – metastatic colorectal cancer
- Severe nausea & vomiting
Neurotoxicity- dose limiting.
Antimetabolites
Folic Acid Analogs
Purine Analogs
Pyrimidine Analogs
Methotrexate
Mercaptoguanine
Fluorouracil
Trimetrexate
Pemetrexed
Thioguanine
Fludarabine Phosphate
Cladribine
Cytarabine
Gemcitabine
Capecitabine
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
Antimetabolits: sites of drug action
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.
Mechanism of Resistance
1. Decreased drug
transport
2. Altered DHFR
3. Decreased
polyglutamate
formation
4. Increased levels
of DHFR
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
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.
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
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
4) Fludarabime:- CLL, hairy cell leukemia, indolent
NHL high doses – encephalopathy, blindness
and death.
5) Hairy cell leukemia, CLL, NHL
Enzyme inhibitors
Topoismerase inhibitors
Anthracy clines
6) Etoposide
1) Damorubicin
7) Irinotecarn
2) Doxorubicin
8) Topotecam
3) Epirubicin
4) Idraubicin
5) Mitoxantrone
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
Doxorubicin
-
Used in Many Cancer
Carditoxi city
-  Acute
 Chronic
 DEXRAZOXANE
“ Radiation recall reaction”