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

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

TrimetrexatePemetrexed

ThioguanineFludarabine PhosphateCladribine

Cytarabine GemcitabineCapecitabine

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 DHFR3. 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

Anthracy clines

1) Damorubicin

2) Doxorubicin

3) Epirubicin

4) Idraubicin

5) Mitoxantrone

Topoismerase inhibitors

6) Etoposide

7) Irinotecarn

8) Topotecam

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”