Cladribine

Absorption

Oral bioavailability is 34 to 48%.

Toxicity

Symptoms of overdose include irreversible neurologic toxicity (paraparesis/quadriparesis), acute nephrotoxicity, and severe bone marrow suppression resulting in neutropenia, anemia and thrombocytopenia.

Description

Cladribine, an adenosine deaminase inhibitor, was introduced in the United States as a single intravenous treatment for hairy cell leukemia. The incorporation of a chlorine atom at the 2-position of deoxyadenosine renders cladribine more resistant to enzymatic attack by adenosine deaminase, resulting in a more prolonged cytotoxic effect. Cladribine efficiently crosses lymphocyte and monocyte cell membranes and is metabolized in cells to the biologically active triphosphate, which inhibits DNA synthesis. While most antineoplastic drugs are active primarily against dividing cells, cladribine destroys both resting and proliferating cells. Its potential uses in the treatment of autoimmune hemolytic anemia, multiple sclerosis, chronic lymphocytic leukemia and various lymphomas have also been evaluated.

Chemical properties

White Crystalline Solid

Originator

Johnson & Johnson (U.S.A.)

The Uses of Cladribine

It is a substituted purine nucleoside with antileukemic activity

The Uses of Cladribine

2-Chloro-2′-deoxyadenosine (2-CdA) is a chlorinated purine nucleoside with activity against lymphoproliferative disorders, such as hairy cell leukemia (HCL) and multiple myeloma (MM). 2-CdA resists ADA degradation and is phosphorylated to CdATP in lymphocytes. CdATP incorporation into DNA induces strand breaks and the activation of apoptosis. 2-CdA may also be used in studies involving the inhibition of DNA polymerase(s).
Cladribiane, like fludarabine, is a prodrug that is must be phosphorylated intracellularly to the monophosphate by the nuclear/cytosol enzyme deoxycytidine kinase (dCK) and possibly by the mitochondrial enzyme deoxyguanosine kinase (dGK).

Indications

For the treatment of active hairy cell leukemia (leukemic reticuloendotheliosis) as defined by clinically significant anemia, neutropenia, thrombocytopenia, or disease-related symptoms. Also used as an alternative agent for the treatment of chronic lymphocytic leukemia (CLL), low-grade non-Hodgkin's lymphoma, and cutaneous T-cell lymphoma.

Background

An antineoplastic agent used in the treatment of lymphoproliferative diseases including hairy-cell leukemia.

What are the applications of Application

2-Chloro-2′-deoxyadenosine is an apoptosis inducer

Definition

ChEBI: 2'-Deoxyadenosine in which the hydrogen at position 2 on the purine ring has been substituted by chlorine. It inhibits the synthesis and repair of DNA, particularly in lymphocytes and monocytes, and is used as an antimetabolite antineoplastic drug for the treatment of lymphoid malignancies including hairy-cell leukaemia and chronic lymphocytic leukaemia.

Indications

Cladribine (Leustatin) is a synthetic purine nucleoside that is converted to an active cytotoxic metabolite by the enzyme deoxycytidine kinase. Like the other purine antimetabolites, it is relatively selective for both normal and malignant lymphoid cells and kills resting as well as dividing cells by mechanisms that are not completely understood.
The drug is highly active against hairy cell leukemia, producing complete remissions in more than 60% of patients treated with a single 7-day course. Activity has also been noted in other low-grade lymphoid malignancies. The major side effect is myelosuppression.

Manufacturing Process

Manufacturing process for Cladribine includes these steps as follows: Preparation of 2',3',5'-O-triacetyl guanosine;Preparation of 9-(2',3',5'-O-triacetyl-β-D-ribofuranosyl)-2-amino-6- chloropurine;Preparation of 9-(2',3',5'-O-triacetyl-β-D-ribofuranosyl)-2,6-dichloropurine;Preparation of 2-chloroadenosine;Preparation of 2-chloro-(3',5'-O-tetraisopropyldisiloxyl)adenosine; Preparation of 2-chloro-2'-O-phenoxythiocarbonyl-(3',5'-O-tetraisopropyldisiloxyl)adenosine; Preparation of 2-chloro-2'-deoxy-(3',5'-O-tetraisopropyldisiloxyl)adenosine; Preparation of 2-chloro-2'-deoxy-adenosine.

brand name

Leustatin (Ortho Biotech).

Therapeutic Function

Cytostatic

General Description

The drug is available in a 10-mg or 10-mL single-use vialfor IV use. Cladribine is used for chronic lymphocyticleukemia, hairy cell leukemia, and non-Hodgkin’s lymphoma.The mechanism of action of this purine deoxyadenosineanalog involves incorporation into DNA resultingin inhibition of DNA chain extension and inhibitionof DNA synthesis and function. This incorporation intoDNA occurs via the triphosphate metabolite active species.The 2-chloro group on the adenine ring produces resistanceto breakdown by adenosine deaminase. Resistance to the anticancereffects can occur because of decreased expressionof the activating enzyme or overexpression of the catabolicenzymes. Oral bioavailability is variable and averages about50%. The drug crosses the blood-brain barrier; however,CSF concentrations reach only 25% of those in plasma. Thedrug is selectively activated inside the cell, and intracellularconcentrations of phosphorylated metabolites exceed thosein plasma. Toxicities include myelosuppression, neutropenia,immunosuppression, fever, nausea, and vomiting.

Biochem/physiol Actions

Deoxyadenosine analog resistant to adenosine deaminase; antileukemic with immunosuppressive activity

Pharmacokinetics

Cladribine is a synthetic purine nucleoside that acts as an antineoplastic agent with immunosuppressive effects. Cladribine differs structurally from deoxyadenosine only by the presence of a chlorine atom at position 2 of the purine ring, which results in resistance to enzymatic degradation by adenosine deaminase. Due to this resistance, cladribine exhibits a more prolonged cytotoxic effect than deoxyadenosine against resting and proliferating lymphocytes. Cladribine is one of a group of chemotherapy drugs known as the anti-metabolites.?Anti-metabolites stop cells from making and repairing DNA, which are processes that are necessary for cancer cells to grow and multiply.

Clinical Use

Antineoplastic agent:
Hairy cell leukaemia (HCL)

Chronic lymphocytic leukaemia (CLL) in patients who have failed to respond to standard regimens.

Drug interactions

Potentially hazardous interactions with other drugs
Antipsychotics: avoid with clozapine - increased risk of agranulocytosis.
Antivirals: avoid with lamivudine.
Caution when administering with any other immunosuppressive or myelosuppressive therapy

Metabolism

Metabolized in all cells with deoxycytidine kinase activity to 2-chloro-2'-deoxyadenosine-5'-triphosphate

Metabolism

Cladribine is extensively distributed and penetrates into the CNS. Cladribine is phosphorylated within cells by deoxycytidine kinase to form 2-chlorodeoxyadenosine- 5′-monophosphate which is further phosphorylated to the diphosphate by nucleoside monophosphate kinase and to the active metabolite 2-chlorodeoxyadenosine-5′- triphosphate (CdATP) by nucleoside diphosphate kinase. CdATP inhibits DNA synthesis and repair, particularly in lymphocytes and monocytes
There is little information available on the route of excretion of cladribine in man. An average of 18% of the administered dose has been reported to be excreted in urine of patients with solid tumours during a 5-day continuous intravenous infusion.

storage

Store at +4°C