Pharmacology of Chemotherapy agents

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Pharmacology of Chemotherapy agents

• David Samuel PharmD BCOP

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History

• Paul Ehrlich coined the term Chemotherapy
  during work with antibacterial agents. Term now
  applied to anti-cancer agents
• 1942 Louis Goodman MD and Alfred Gilman PhD
  recruited by Department of Defense to
  investigate therapeutic applications of chemical
  warfare based on observations that exposure to
  Mustard gas caused lymphoid and myeloid
  suppression.
• Recruited Gustov Linskog MD, a thoracic surgeon
  and injected Mechlorethamine into a patient with
  Non-Hodgkins lymphoma. Patient had a dramatic
  response, but of short duration.
• 1946 Published their landmark results in the
  Journal of the American Medical Association.
  Reprinted in JAMA in 1984.

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History

• 1948 Sydney Farber MD at Harvard Medical School
  studied effects of Folic Acid on leukemic cells
  based on the observation that Folic Acid caused
  proliferation in pediatric ALL patients.
• Farber along with Harriett Kilte at Lederle Labs
  synthesized Folic Acid analogs Aminopterin and
  Amethopterin (Methotrexate, MTX) . This was the
  beginning of rational drug design. Began studying
  effects of MTX in pediatric ALL.
• 1950s Introduction of combination chemotherapy

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Etiology

• Environmental factors
• Food additives (nitrites)
• Pollution (asbestos)
• Occupational (benzene)
• Industrial (hydrocarbons soot)
• Lifestyle and other factors
• Tobacco (leading cause of NSCLC)
• Alcohol (beer rectal cancer)
• Diet (obesity)
• Viruses (HPV, HIV)

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Etiology

• Knudsons two hit theory (Rb gene) 1971
• R. White clonality (APC gene) 1987

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Goals of therapy

• Curative
• Childhood leukemia
• Testicular Cancer
• Hodgkins disease
• Stage I through III Breast Cancer
• Palliative (slow down disease progression)
• Prostate Cancer
• Multiple Myeloma, indolent lymphomas
• Head Neck
• Stage IV Breast Cancer
• NSCLC

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Treatment Modalities

• Surgery ( localized disease, staging, palliation,
  endocrine ablation, debulking)
• Radiation (localized disease, debulking,
  palliation)
• Chemotherapy
• Immunotherapy
• Combined Modality (employ 2 or more modalities to
  increase response)
• Neoadjuvant prior to definitive local therapy
  (surgery) potentially organ sparing
• Adjuvant following definitive therapy

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Tumor growth concepts

• Growth Fraction
• Doubling time
• Early stages high growth fraction, short
  doubling times
• Late stages low growth fraction, long
  doubling times
• Chemotherapy most effective when growth
  fraction is high.

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Gompertzian growth

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Chemotherapy considerations

• Tumor cells undergo the same cellular processes
  (replication, division)
• Tumor cells dont necessarily grow faster than
  normal cells
• Non-specific agents interfere with these
  processes
• Ideal chemotherapy is toxic to tumor cells but
  spares normal cells
• Cell cycle specific agents antimetabolites,
  Vinca alkaloids
• Cell cycle non-specific agents Doxorubicin,
  Cisplatin
• Give the most effective therapy early in disease
  pricess

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Purposes of Chemotherapy

• Primary shrink or eliminate tumor
• Neoadjuvant make tumor more amenable to other
  therapies
• Adjuvant eradicate micro metastasis
• Palliation symptom control
• Response to Chemotherapy
• CR complete disappearance for at least 1 month
• PR 50 or gt reduction in tumor size or markers
  and no new disease for 1 month
• SD no reduction or growth
• Progression 25 increase in tumor size

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Adjuvant chemotherapy

• Risk of recurrence despite surgical resection
• Failure of chemotherapy to cure after recurrence
• Cancers most sensitive to chemotherapy in early
  stages
• Decreased probability of biochemical resistance
• Disadvantage exposure of truly cured patients
  to chemotherapy
• Late complications sterility, risk of
  secondary malignancy

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Kinetic basis of Chemotherapy

• Fractional kill hypothesis
• Tumor accumulates between cycles
• chemotherapy follows exponential log kill
  (never reaches zero)
• Phase specific agents schedule dependent
• more effective when given in divided doses at
  repeated intervals
• more effective in tumors with high growth
  fraction
• Phase non-specific agents
• exert effects throughout the cell cycle
• dose or concentration dependent effects
• may have effect in resting phase
• Biochemical heterogeneity

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Determinants of response

• In-vitro testing
• Inherent sensitivity of tumor
• Variable expression of metabolizing enzymes
• Molecular targeting
• Pharmacokinetic determinants AUC dosing

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Drug interactions

• 20-30 of interactions are caused by drugs
• Clinically relevant in up to 80 of elderly
• Complex pharmacological profile
• Narrow therapeutic window, Steep dose-toxicity
  curve
• PK and PD inter-patient variability
• Failure to recognize leads to over dosing or
  under dosing

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Drug interactions

• Pharmaceutical
• Cisplatin Mesna results in covalent adduct
• Mitomycin in Dextrose containing fluids
• 5FU dilution in low pH
• Precipitation of Taxanes, VP-16
• IL-2 adsorption
• Pegylation of DOX AUC is 300 X greater,
  Clearance decreased 250 X
• Polyoxyethylated Castor oil versus Tween 80 and
  Paclitaxel (in-vitro)
• Paclitaxel and Doxorubicin (polyoxyethylated
  castor oil)

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Drug interactions

• Pharmacokinetic
• Absorption 6-MP allopurinol 6-MP
  Azathioprine (25-33 dose reduction required)
• Distribution liposomal preparations alter
  toxicity profile
• Metabolism CyP3A4 Taxanes,
  Cyclophosphamide, IFEX, antifungals, protease
  inhibitors, Benzodiazepines, Anticonvulsants
• CyP2B6 Cyclophosphamide, Thiotepa
• Cyp2D6 DOX, Vinca alkaloids
• VCR Itraconazole
• Sorivudine Tegafur (Japan)
• Sequence Cisplatin Paclitaxel (25 lower
  clearance)
• Elimination NSAIDs and MTX or Cisplatin

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Drug interactions

• Pharmacodynamic
• Cisplatin with gemcitabine
• Cisplatin with topotecan
• 5FU with Leucovorin
• Platelet sparing effect of Carboplatin with
  Taxol
• OTC medications
• St. Johns wart potent inducer - avoid with
  CPT-11

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Prediction of drug response

• Selection of drugs based on previous trials
• Human tumor xenograft studies
• Biochemical tests asparaginase, DHFR
• Molecular targeting TKIs
• EGFR targeted medications

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Combination therapy

• Improved response
• Decrease resistance (p-glycoprotein, MDR
  phenotypes)
• Non-overlapping toxicity

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Classes of drugs

• Direct DNA interacting agents covalent adducts
• Nitrogen mustard, Cyclophosphamide, Ifosfamide,
  Cisplatin
• Antitumor antibiotics and Topoisomerase
  inhibitors
• Doxorubicin, Bleomycin, Dactinomycin
• Antimetabolites
• ARA-C, MTX, 5-FU
• Mitotic spindle poisons
• Taxanes, Vinca alkaloids, VP-16
• Hormonal agents
• Tamoxifen, LHRH agonists
• Molecular targeted therapies
• TKI Gleevec, Monoclonal antibodies

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Classes of drugs

• Cytokines
• IL-2, Interferons
• Immune modulators
• Levamisole, BCG
• Differentiation inducers
• Retinoids
• Glucocorticoids
• immunosuppressive, lympholytic
• L-asparaginase
• Depletes asparagine

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Classes of drugs

• Monoclonal antibodies - Unconjugated
• Rituximab - (Rituxan) - lymphoma (CD20)
• Trastuzumab (Herceptin) - breast (her2)
• Alemtuzumab (Campath) CLL (CD52)
• Monoclonal antibodies congugated
• Ibritumomab (Zevalin) Y90 labeled
• Tositumomab (Bexxar) I131 labeled
• Immunotoxin
• Gemtuzumab (Mylotarg) AML (CD33)

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New targeted therapies

• Tyrosine Kinase Inhibitors Gleevec, Iressa
• Cyclin Dependent Kinase inhibitors Flavoperidol
• Farnesyl transferase inhibitors R115777
• Matrix Metalloproteinase inhibitors NSC683551
• Proteosome inhibitor Bortezomib (Velcade)
• DNA demethylating agent 5-Azacytidine (Vidaza)