1. Alkylating agents: Platinum analogs Nitrogen Mustards Carboplatin
Cisplatin
Oxaliplatin
Triazenes
Dacarbazine
Procarbazine
Temozolomide
Nitrogen Mustards
Bendamustine
Cyclophosphamide
Estramustine
Ifosfamide
Mechlorethamine
Melphalan

2. Miscellaneous
13) Busulfan
14) Chlorambucil
15) Lomustine

3. Alkylating agents Nitrosoureas
-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

4. Pharmacological effects :
-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

5. CYCLOPHOSPHAMIDE
NITROSOUREAS:
Not cross resistant with other alkylating agents
Enter BBB- lipid soluble – Brain tumors
Oral administration
STREPTOZOCIN

6. 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

8. NON CLASSICAL ALKYLATING AGENTS:
PROCARBAZINE: Hodgkin's, Non – Hodgkin's, Brain
-Microsomal enzymes – azoprocarbazine + H2O2
One metabolite – weak MAOI
Increase risk of secondary cancer

9. DACARBAZINE
Activation in liver  monomethyl derivative  diazomethane,  methyl Carbonium ion  cytotoxic
Malignant melanoma, HL, Soft tissue sarcomas, neuroblastoma.
Potent vesicant

10. 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.

11. -Oxaliplatin + 5-FU + leucovorin – FOLFOX regimen – metastatic colorectal cancer
- Severe nausea & vomiting
Neurotoxicity- dose limiting.

12. Trimetrexate Pemetrexed Cytarabine Thioguanine Gemcitabine
Capecitabine
Thioguanine
Fludarabine Phosphate
Cladribine

13. Anti metabolites:
Folate antag:-
Methotrexate
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

14. Antimetabolits: sites of drug action

15. 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.

16. Mechanism of Resistance
1. Decreased drug transport
2. Altered DHFR
3. Decreased polyglutamate formation
4. Increased levels of DHFR

17. 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

18. 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.

19. Anti-metabolites:-
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

20. 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

21. 4) Fludarabime:- CLL, hairy cell leukemia, indolent
NHL high doses – encephalopathy, blindness
and death.
5) Hairy cell leukemia, CLL, NHL

22. Enzyme inhibitors
Anthracy clines
Damorubicin
Doxorubicin
Epirubicin
Idraubicin
Mitoxantrone
Topoismerase inhibitors
Etoposide
Irinotecarn
Topotecam

23. 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

24. Doxorubicin - Used in Many Cancer
Carditoxi city  Acute
 Chronic
 DEXRAZOXANE
“ Radiation recall reaction”