DOUBLE WHAMMY: Is there a common switch to avoid anticancer drugs

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DOUBLE WHAMMY Is there a common switch to avoid
anti-cancer drugs?

• Adam Coates James Greenwood

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AIMS OBJECTIVES

• Understand the functions of P-gp and P450
• Understand Double Whammy effect of chemotherapy
• Be able to explain how this leads to Multidrug
  Resistance
• Be aware of the problems encountered with using
  P-gp inhibitors
• Understand the therapeutic benefits of 3rd
  generation drugs

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P-Glycoprotein (Pgp)

• ATP-dependant efflux drug transporter.
• Expressed in normal tissues- GI epithelium
• 
  Canicular
  membrane of liver
• 
  kidney
• 
  Capillary
  endothelial cells in CNS
• Broad substrate specificity.
• Plays a key role in absorption, distribution,
  elimination of many drugs..
• including ANTICANCER AGENTS!

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Cytochrome P-450 (CYP)

• Mixed-function monooxygenase enzyme.
• 500 amino acids and a hæm group at the active
  site.
• More than 6000 distinct cytochrome P450
  sequences are known and officially named.
• CYP3A is the primary subfamily responsible for
  phase 1 metabolism of gt50 of drugs administered
  to humans (Benet et al, 1996a).
• CYP3A4 most prominent CYP in humans. 30 of
  CYPs liver
• 70 of CYPs intestine
• Has broad substrate specificity, inc. many
  chemotherapy agents.

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DOUBLE WHAMMY!

• Chemotherapy treatment has been proved to CAUSE
  an UPREGULATION of P-gp AND P450.
• An inherent defence mechanism - useful when
  dealing with standard toxic chemicals, but
  counterproductive in chemotherapy
• P-gp (MDR1) gene expression can be rapidly
  activated in human tumours after transient in
  vivo exposure to cytotoxic chemotherapy.
• In a study of sarcoma pulmonary metastases, a
  3-15 fold increase in MDR1 RNA expression, was
  observed after lung perfusion with doxorubicin,
  AFTER 50 MINS!! (1)

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Why this is bad

• Means Chemotherapy is becoming ineffective as
  the course of treatment progresses.
• Greater P-gp efflux cellular level
• Greater p450 metabolism - systemic level
• Multi Drug Resistance developing

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P-gp inhibitors

• Need to inhibit P-gp pumps. I.e. keep drug in the
  malignant cell.
• Clinically not as simple as that
• 1980s- Early (1st generation) drugs e.g.
  Cyclosporin, verapamil. Non-spec to p-gpToxic
  levels!
• 2nd generation e.g. Valspodar, Biricodar. More
  potent, less toxic
• But

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BUT

• The genes of the P-gp and p450 families share
  overlapping regulatory elements
• Infact, many of the cytotoxic agents that are
  substrates for P-gp are also substrates for the
  p450 isoenzyme 3A4
• Therefore you also get inhibition of
  p450-mediated metaboism
• Can lead to SYSTEMIC TOXICITY.
• OR- lack of activation of chemotherapy drugs

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Whats The Answer Then?

• Need a drug which balances therapeutic effects
  with those of potential toxicity. Therefore,
  ideally targeting the inhibition of Pgp, with
  minimal inhibition of CYP3A
• Studies have shown that 3rd generation P-gp
  inhibitors-
• Specifically and potently inhibit P-gp function
• And yet dont affect CYP3A4 at relevant
  concentrations
• Therefore, chemotherapy doses DONT need to be
  reduced.

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Clinical Trials 3rd generation

• Tariquidar (2) Zosuquidar (3)
  Laniquidar (4)
• Trials show can be given with full therapeutic
  doses of cytotoxic agents, with minimal
  interference with of the pharmokinetics of the
  cytotoxic agents
• This approach should avoid MDR and improve the
  prognosis for cancer patients.
• Preliminary results offer new hope that this goal
  might be achieved

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Summary

• Anticancer drugs not only target neoplastic
  cells, they also up-regulate the expression of
  the ABC transporter, P-glycoprotein. The
  consequence of this is that neoplasm become MDR
  as the ABCB1 is able to efflux chemotherapeutic
  agents. At the same time the Cytochrome P450
  enzymes are also up-regulated, so that overall
  not only is the drug being removed from cells, it
  is also being metabolised and subsequently
  eliminated producing a DOUBLE WHAMMY inhibition
  on the action of anti-cancer drugs.
• Where research has gone looking to drugs to
  co-administer with chemotherapeutic agents, which
  will inhibit the effects of P-gp and not have a
  dual inhibition on the action of cytochrome
  p450Drugs have been found
• BUT the long term effects are not known, as
  trials are still going on..
• FUTURE Gene therapy identifing the gene, which
  controls expression of Pgp by neoplasm and
  modifying expression so that rather than cancers
  expressing the gene, surrounding normal cells
  do!!!

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References

• 1) Abolhoda A, Wilson AE, Ross H, et al. Rapid
  activation of
• MDR1 gene expression in human metastatic
  sarcoma after in vivo
• exposure to doxorubicin. Clin Cancer Res.
  199953352-3356.
• 2) Roe M, Folkes A,Ashworth P, et al. Reversal of
  P-glycoprotein
• mediated multidrug resistance by novel
  anthranilamide derivatives.
• Bioorg Med Chem Lett. 19999595-600
• 3) Starling JJ, Shepard RL, Cao J, et al.
  Pharmacological characterization of LY335979 a
  potent cyclopropyldibenzosuberane modulator of
  P-glycoprotein. Adv Enzyme Regul. 199737335-347
• 4) van Zuylen L, Nooter K, Sparreboom A, et al.
  Development of multidrug-resistance convertors
  sense or nonsense? Invest New
• Drugs. 200018205-220.
• Papers used extensively-
• Hilary Thomas, MA, FRCP, FRCR, PhD, and Helen M.
  Coley, PhD Overcoming Multidrug Resistance in
  Cancer An Update on the Clinical Strategy of
  Inhibiting P-Glycoprotein.Cancer control Journal
  of the Moffitt cancer centre.
• Christoph Wandel, Richard B. Kim, Shama Kajiji,
  F. Peter Guengerich, Grant R. Wilkinson and
  Alastair J. J. Wood. P-Glycoprotein and
  Cytochrome P-450 3A Inhibition Dissociation of
  Inhibitory Potencies.