In ALL after 14 days of treatment the number of leukemic cells is 10¹² & number of resistant leukemic cells is 10⁷.

Mechanisms of drug resistance

• Decreased uptake
• Increased catabolism
• Decreased transformation of prodrug
• Modification of drug target
• Increase in DNA repair
• Resistance to drug induced apoptosis

Multi Drug Resistance

• Tumor cells resistant to a class of drug are usually also cross resistant to chemotherapy with different target
• Efflux Pumps such as ATP – binding cassette (ABC) transport protein play major role in development of multidrug resistance
• ABC proteins are responsible for energy dependent efflux of plant / microbial products, known as xenobiotics

Classification of ABC proteins involved in multidrug resistance in cancer

Structure of ABC unit

• 200 – 250 amino acids
• Contains  – Walker  A & B motifs
• 6 transmembrane domains
• Drug induced conformational change creates a hydrophobic pocket, able to bind and transport the substrate out of cell.
• Monoclonal antibodies for detection of P-gp are available & are used in flow cytometry.
• Pgp in various leukemias
  • AML
    • 1/3^rd - ½ cases are positive during diagnosis, especially in elderly
    • Expressed on AML with ‘poor’ cytogenetic features
    • Never expressed on AML-M3
  • Childhood ALL 
    • <10% are positive at diagnosis
  • Adult ALL
    • 15-20% positive at diagnosis
  • CLL – Very low expression
  • CML – Low positivity but Imatinib is substrate for Pgp

• MRP family (ABCC 1-6)
  • They are transporters of
    • Organic onions such as methotrexate
    • Neutral organic drugs conjugated to acidic ligands (GSH) such as cisplatin& arsenic
  • Their presence can be assessed by flow cytometry using monoclonal antibodies against MRP
• ABCG2
  • Involved in active efflux of mitoxantrone.
• Lung resistance protein / major vault protein
  • Vaults mediate bidirectional transport of a variety of substrates between the nucleus and cytoplasm.

Resistance to drug induced apoptosis

• p53 mutation
  • Normally it is activated in response to DNA damage and stops the cell in G1 phase
  • If DNA repair cannot be done then it induces apoptosis
  •  In  case of non functional p53, the threshold of DNA damage leading to apoptosis increases and this contributes to drug resistance
• Bcl-2 family- Bcl-2 and Bcl XL
  • They are antiapoptotic
  • Their Overexpression protects tumor lines from toxicity of several chemotherapy drugs
• BCR-ABL
  • Confers resistance to genotoxic agent induced apoptosis ( Ara C, Daunorubicin, VP-16 etc)

Reversal of MDR

• Pgp inhibition
  • Verapamil, amiodarone, quinine, Cyclosporin A,
  • Pgp modulator- PSC-833 (Analogue of Cyclosporin D)- 10mg/kg/day, continuous  IV infusion, after a loading dose of 2mg/kg over 2hrs
• LY 335979- Quinalone derivative
• BCRP pump inhibition
  • GG 120918- Derivative of acridonecarboxamide
• Modulator of Pgp and MRP1
  • VX-710 (Biricodor)- Pipecolinate derivative
• Restoration of drug induced apoptosis
  • Bcl antisense complementary codons- G 3139- Given subcutaneously
• RAS inhibition
  • To be active RAS has to be farnesylated
  • So inhibitors of farnesyltransferase are used to counter act drug resistance.