LEUKERAN

Indications

• Chronic lymphocytic leukaemia
• Hodgkin's lymphoma
• Non-Hodgkin's lymphoma
• Mycosis fungoides (initiated by a specialist)

Dosage

Children: Consult local protocols for specific dosing guidance; dosing in children must be determined by a specialist based on clinical condition and response.

Adults: Consult local protocols for specific dosing guidance, as chlorambucil dosing can vary based on the condition being treated and individual patient circumstances.

Mechanism of action

Chlorambucil acts primarily as an alkylating agent, attaching alkyl groups to DNA bases. This results in DNA fragmentation and the formation of cross-links between DNA strands, preventing DNA separation necessary for replication and transcription. Additionally, it induces mispairing of nucleotides, leading to mutations. Its major metabolite, phenylacetic acid mustard, also contributes to its antineoplastic activity. Chlorambucil has immunosuppressive effects, particularly by suppressing lymphocyte proliferation.

Pharmacodynamics

Chlorambucil is an antineoplastic agent that disrupts DNA functionality in cancer cells. By cross-linking guanine bases in DNA, it prevents the necessary uncoiling and separation of DNA strands for replication, effectively halting tumor growth. As an alkylating agent, it is considered cell cycle-nonspecific, meaning it can affect cells at any stage of the cell cycle. Its immunosuppressive properties further assist in its effectiveness against certain malignancies.

Pharmacokinetics

Chlorambucil is absorbed following oral administration and undergoes extensive hepatic metabolism, leading to the formation of active metabolites. It has a long half-life, allowing for sustained action, though individual variability can occur. It is eliminated primarily via the liver, and its pharmacokinetic profile may be influenced by patient factors such as liver function.

Contra-indications

• Hypersensitivity to chlorambucil or any components of the formulation
• Severe bone marrow suppression
• Active infections

Adverse effects

• Anaemia
• Leucopenia
• Thrombocytopenia
• Nausea
• Vomiting
• Diarrhoea
• Skin reactions
• Seizures
• Secondary malignancies, particularly acute leukaemia
• Amenorrhoea
• Azoospermia

Interactions

• Other alkylating agents
• Live vaccines (increased risk of infections)
• Contraceptives (effectiveness may be reduced)

Precautions

• History of epilepsy (increased seizure risk)
• Hepatic impairment (caution required)
• Renal impairment (monitor for toxicity)
• Avoid contact with mucous membranes
• Use in women of childbearing potential requires contraception advice

Pregnancy

Manufacturer advises to avoid use due to potential toxicity; contraindicated in pregnancy.

Breast-feeding

Discontinue breastfeeding during treatment.

Storage

Store in a refrigerator (2–8 °C); consult product literature for specific storage instructions.

Formulations

• Chlorambucil 2 mg tablets

Mechanism of action

Alkylating agents work by three different mechanisms: 1) attachment of alkyl groups to DNA bases, resulting in the DNA being fragmented by repair enzymes in their attempts to replace the alkylated bases, preventing DNA synthesis and RNA transcription from the affected DNA, 2) DNA damage via the formation of cross-links (bonds between atoms in the DNA) which prevents DNA from being separated for synthesis or transcription, and 3) the induction of mispairing of the nucleotides leading to mutations. As an alkylating agent, chlorambucil interferes with DNA replication and transcription of RNA, and ultimately results in the disruption of nucleic acid function. In vitro studies have shown that the major metabolite of chlorambucil (phenylacetic acid mustard), which is also a bifunctional alkylating compound, has antineoplastic activity against some neoplastic human cell lines that is approximately equal to that of chlorambucil. Therefore, the major metabolite of chlorambucil may contribute to the in vivo antitumor activity of the drug. Chlorambucil also possesses some immunosuppressive activity, principally due to its suppression of lymphocytes. The drug is the slowest acting and generally least toxic of the presently available nitrogen mustard derivatives. A marked transient increase was observed in ribonucleotide reductase activity within 2 hr of exposing BALB/c 3T3 mouse cells to DNA damaging concentrations of chlorambucil. Elevations in activity were accompanied by transient increases in the mRNA levels of both genes (R1 and R2) that code for ribonucleotide reductase. Only the protein for the limiting component for enzyme activity R2 was significantly elevated in chlorambucil treated cultures. The chlorambucil effects upon activity and regulation of ribonucleotide reductase occurred without any detectable changes in the rate of DNA synthesis, as would be expected if the elevation in enzyme activity is required for DNA repair. The chlorambucil-induced elevations in R1 and R2 message levels were blocked by treatment of cells with actinomycin D or the tumor promoter 12-O-tetradecanoylphorbol-13-acetate indicating the importance of the reductase transcriptional process in responding to the action of chlorambucil and providing evidence for the involvement of a protein kinase C pathway in the regulation of mammalian ribonucleotide reductase. In addition to the chlorambucil-induced elevations in enzyme activity, message, and protein levels, the drug was also shown to be an inhibitor of ribonucleotide reductase activity in cell-free preparations. Both R1 and R2 proteins were targets for chlorambucil, in keeping with the known alkylating abilities of the drug. /ALTERNATIVE and IN VITRO TESTS/ Reaction of one of the two chloroethyl groups of chlorambucil with the N7 position of guanine or adenine of double-stranded DNA leads to the formation of mono-adducts. These are repaired rapidly in an error-free fashion by methylguanine methyltransferase (sometimes called alkylguanine alkyltransferase). However, some cells lack this repair activity, usually because of silencing of the corresponding gene, and the unrepaired DNA mono-adduct then forms a complex with mismatch-repair enzymes. The subsequent inhibition of DNA replication can eventually induce DNA breakage. The second chloroethyl group of the DNA mono-adduct with chlorambucil can interact with proteins but more importantly, because of its juxtaposition to other bases in the major groove of DNA, it can react with a DNA base to form an interstrand DNA cross-link. This DNA crosslink complex is quite stable, and its repair requires nucleotide excision repair factors (such as xeroderma pigmentosum complementation group F-excison repair cross-complementing rodent repair deficiency, complementation group, 1-XPF-ERCC1) that act slowly by homologous recombination. The DNA cross-link attracts several binding proteins, probably the BRCA1 and BRCA2 proteins, Fanconi anemia gene product, and Nijmegen b

Pharmacodynamics

Chlorambucil is an antineoplastic in the class of alkylating agents that is used to treat various forms of cancer. Alkylating agents are so named because of their ability to add alkyl groups to many electronegative groups under conditions present in cells. They stop tumor growth by cross-linking guanine bases in DNA double-helix strands - directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. In addition, these drugs add methyl or other alkyl groups onto molecules where they do not belong which in turn inhibits their correct utilization by base pairing and causes a miscoding of DNA. Alkylating agents are cell cycle-nonspecific. Alkylating agents work by three different mechanisms all of which achieve the same end result - disruption of DNA function and cell death.