Alkylating Agents

Alkylating agents are the broad spectrum agennts.

Chemistry

• Different reactive moiety: Bis (chloroethyl) amine / ethyleneimine / nitrosourea, responsible for different actions
• Either two or more of these are present known as Bi-  / Poly-functional

Mechanism of action

1. These molecules undergo intracellular circulization forming Etyleneimonium ion reacting with cellular components, further change into carbonium ion, alkylating cellular components
2. In cell, different groups are present to which alkylating agents bind mainly Imidazole / amino / OH / COOH / SH / PO₄  groups
3. Nitrosourea – carbamoylation of lysine
4. DNA – N7 G / N1,N3 A / N3 C / O6 G
5. Interfere DNA synthesis, replication, transcription, alkylate one base causing joining of two bases.
6. DNA cross-linking, breaks
7. Interfere RNA, protein synthesis

Pharmacokinetics

• Given Oral / IV, metabolized by microsomal enzymes, mainly conjugated and excreted out.

Resistance

Different mechanisms:

1.      Decreased permeation into cells
2.      Increased DNA repair by cells
3.      Increased production of glutathione (GL- S transferase) leading to glutathione conjugation, making alkylating agent ineffective.

Toxicity

Same as in general toxicity with some additional effects

Uses

1. Blood,
2. Bone marrow
3. Lymphomas,
4. Breast,
5. Ovarian,
6. Gastero-esophageal,
7. Colorectal,
8. Lung,
9. Bladder,
10. Head & neck,
11. Melanoma,
12. Soft tissue sarcoma,
13. Neuroblastoma

Cyclophosphamide

Prodrug, commonly used

Pharmacokinetics – given orally or I/V

                                    – metabolism occurs inliver

Metabolism Of Cyclophosphamide

Acrolien has side effect of hemorrhagic cystitis. Liver is protected by inactivation into 4 ketocyclophosphamide and carboxyphosphamide.

Resistance

Same as other alkylating agents

Toxicity – general

Hemorrhagic cystitis –specific effect

Provide sufficient hydration.

Mesna given –organosulphur compound which detoxifies metabolites in bladder and prevents.

Uses 

1. Breast,
2. Ovarian,
3. CLL,
4. Non-hodgkin’s lymphoma,
5. Wilms’tumor

Busulphan

• Used in CML

Nitrosoureas

• Carmustine,
• Lomustine,
• Streptozocin

Mechanism of Action

Alkylation (same as other alkylating agents)

–  Carbamoylation of lysine

–  No cross-resistance

Pharmacokinetics

–given orally or I/V

-non-enzymatic decomposition

-highly lipid soluble

Toxicity

STREPTOZOCIN has minimal bone marrow toxicity

Uses

• Insulinoma,
• Brain,
• Lymphomas

Platinum Analogs

Cisplatin – Inorganic metal complex

Mechanism of Action – same as alkylating agents

Toxicity – general

–  Nephrotoxicity – hydration by oral I/V fluids

–  Neuropathy

–  Ototoxicity

Uses

a.      Solid tumors
b.      lung / esophageal / gastric / head & neck / testicular / ovarian / bladder

Carboplatin -Second generation

–Less toxic

-May cause myelosuppession

Oxaliplatin   -Third generation

-for those resistant to 1^st and 2^nd generation

-Used in colorectal cancer (FOLFOX)

-Neurotoxicity (acute triggered by exposure to cold)

Chronic adverse effects–dose dependent)

FOLFOX – 5-FU + Oxaliplatin + Leucovorin

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