Medical Pharmacology Chapter 33-34:  Anticancer Drugs

• Antimetabolites

  • Purine Analogues:

    • Cladribine (Leustatin, Mavenclad and others)

      • Cladribine (Leustatin)

         

      • Overview:

        • Cladribine (2-Chlorodeoxyadenosine, Leustatin), an adenosine deaminase (ADA)-resistant. purine analog, with activity against low-grade lymphoproliferative cancer, particularly hairy cell leukemia¹⁰ (leukemic reticuloendotheliosis; the, designation i.e. hairy cell leukemia was based on the "hairy" appearance of malignant B cells).

        • Hairy Cell Leukemia¹¹ (second sourced)

          Attribution: Park J New Approaches to Hairy Cell Leukemia: 2017 Great Debates & Updates in Hematologic Malignancies https://www.youtube.com/watch?v=UNl8RqNOf_Y (4/2017) ImedexCME Youtube Channel:  https://www.youtube.com/channel/UChzdRqqisBHL_DgHGq0COFg

        •  

          "New Approaches to Hairy Cell Leukemia"¹¹

          Attribution: Park J New Approaches to Hairy Cell Leukemia: 2017 Great Debates & Updates in Hematologic Malignancies https://www.youtube.com/watch?v=UNl8RqNOf_Y (4/2017) ImedexCME Youtube Channel:  https://www.youtube.com/channel/UChzdRqqisBHL_DgHGq0COFg

          •  

            Hairy Cell Leukemia⁹

            Figure 1 from reference 9" "Characteristic hairy cell leukemia.  This figure depicts the characteristic malignant cell in the peripheral blood from a patient with hairy cell leukemia. The serrated cytoplasmic border and the nuclear chromatin pattern are readily appreciated on a Wright stain." Grever MR Lozanski G Modern Strategies for Hairy Cell Leukemia Journal of Clinical Oncology 29, no. 5   (February 2011) 583-590. http://ascopubs.org/doi/10.1200/JCO.2010.31.7016

        • Other low-grade lymphoproliferative diseases that may benefit from cladribine treatment include CLL (chronic lymphocytic leukemia) and low-grade non-Hodgkin's lymphoma.

          • Cladribine is also effective in treating multiple sclerosis and childhood leukemia.

        • Cladribine is considered a prodrug, requiring activation following its transport into cells by active nucleoside transport.^1,3  

          • Activation requires phosphorylation steps catalyzed first by deoxycytidine kinase, forming the monophosphate and ultimately the triphosphate form, which can be incorporated into DNA.^1,3  

            • The triphosphate active metabolite inhibits DNA synthesis and DNA repair by means of inhibiting DNA polymerase-α and DNA polymerase-β, respectively.

            • Cladribine triphosphate incorporation into DNA promotes strand breakage as well as NAD and ATP depletion, a trigger for programmed cell death (apoptosis).

              • By contrast to many anti-neoplastic agents, cladribine triphosphate does not require active cell division to exhibited cytotoxicity.

        • Cellular resistance to the action of cladribine triphosphate is likely due to: ^1,3

          • Decreased levels or loss of deoxycytidine kinase (dCK), the enzyme that activates the prodrug parent agent,

          • Cladribine increased amounts of ribonucleotide reductase or

          • Increased active drug efflux, out of the cell, by means of the ABC transporter family member, primarily ABCG2.^1,3  

           

    • Mechanism of Action:

      • Activation of cladribine is dependent on sequential intracellular phosphorylation, reactions catalyzed by deoxycytidine kinase (dCK).⁸

        • The triphosphate metabolite (5'-triphosphate metabolite) is 2-chloro-2'-deoxyadenosine 5-triphosphate (2-CdATP) builds up in cells expressing deoxycytidine kinase at high levels.

        • 2-CdAMP (the monophosphate form) following DNA incorporation causes DNA strand breaks.⁸

          • Furthermore, three sequential Cl-d-AMP (2-Chloro-2'deoxyadenosine monophosphate) residues and DNA prevents strand elongation. ^8,12  

        • Cladribine monophosphate can directly inhibit transcription if it is incorporated into DNA promoter sequences.^8,13 

          • In an in vitro test system binding interactions of the human TATA box-binding protein were disruptive in 2-chlorodeoxyadenosine monophosphate (CldAMP)-substituted TAT box consensus sequences.

            • In such cases in vitro polymerase II transcription was reduced by about one-third compared to control substrates.

            • ["A TATA box is a DNA sequence that indicates where genetic sequence can be read and decoded. It is a type of promoter sequence, which specifies two other molecules were transcription begins. Transcription is a process that produces an RNA molecule from a DNA sequence".] ¹⁴

              • TATA Box Description¹⁵

                Attribtion: Luttysar TATA box description, where W in the TATA box sequence can be either A or T. https://en.wikipedia.org/wiki/File:TATA_box_description.png (10/2017)

                 

        • Cl- dATP (the 5'-triphosphate fludarabine metabolite) also is an effective inhibitor of ribonucleotide reductase (RNR), resulting in an imbalance of deoxyribonucleotide triphosphate pools.⁸

          • A consequence of such imbalance is impairment of DNA synthesis and repair.

        • Cladribine triphosphate may induce apoptosis in certain cells.

          • In these cases the triphosphate analog of cladribine interacts with protease activating factor-1 (PAF-1) and cytochrome C, thus initiating caspase cascade resulting in DNA degradation.⁸

     

    • Absorption, Distribution, Biotransformation, Excretion:¹

      • Cladribine exhibits an oral bioavailability of about 50%. ¹

        • The agent is not FDA approved for oral administration. It is under consideration by the FDA in the oral formulation as a treatment for multiple sclerosis.

      • Cladribine is administered intravenously and is excreted by the kidneys.

        • The terminal t_1/2 is about 7 hours.

        • Because of the importance of renal excretion, cladribine dosages are typically adjusted in accord with the presence and extent of renal dysfunction.

      • Cladribine clearance is about 40 liters/h/m² (children).¹⁶ 

      • Cladribine is able to cross the blood-brain barrier allowing CSF concentrations to reach about 25% of plasma levels.¹

     

    • Toxicity:¹

      • Myelosuppression following cladribine administration is the principal dose-limiting toxic response.

        • Repeated courses of treatments containing cladribine may be associated with thrombocytopenia.

        • Reduced CD4⁺ T-cell levels following cladribine therapy predispose patients to opportunistic infections.

          • A range of other toxic reactions include nausea, fever, infections, fatigue, and tumor lysis syndrome.¹