Transcript Leukemias and Lymphomas

Pharmacology of Chemotherapy agents
David Samuel PharmD BCOP
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-Hodgkin’s 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.
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
Etiology
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Environmental factors
 Food additives (nitrites)
 Pollution (asbestos)
 Occupational (benzene)
 Industrial (hydrocarbons – soot)
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Lifestyle and other factors
 Tobacco (leading cause of NSCLC)
 Alcohol (beer – rectal cancer)
 Diet (obesity)
 Viruses (HPV, HIV)
Etiology
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Knudson’s two hit theory (Rb gene) 1971
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R. White – clonality – (APC gene) 1987
Goals of therapy
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Curative
Childhood leukemia
Testicular Cancer
Hodgkin’s 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
Treatment Modalities
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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
Tumor growth concepts
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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.
Gompertzian growth
Chemotherapy considerations
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Tumor cells undergo the same cellular processes (replication, division)
Tumor cells don’t 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
Purposes of Chemotherapy
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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 > reduction in tumor size or markers and no new disease for 1 month
SD – no reduction or growth
Progression – 25% increase in tumor size
Adjuvant chemotherapy
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Risk of recurrence despite surgical resection
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Failure of chemotherapy to cure after recurrence
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Cancers most sensitive to chemotherapy in early stages
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Decreased probability of biochemical resistance
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Disadvantage – exposure of truly cured patients to chemotherapy
Late complications – sterility, risk of secondary malignancy
Kinetic basis of Chemotherapy
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Fractional kill hypothesis
Tumor accumulates between cycles
chemotherapy follows exponential log kill (never reaches zero)
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Phase specific agents – schedule dependent
more effective when given in divided doses at repeated intervals
more effective in tumors with high growth fraction
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Phase non-specific agents
exert effects throughout the cell cycle
dose or concentration dependent effects
may have effect in resting phase
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Biochemical heterogeneity
Determinants of response
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In-vitro testing
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Inherent sensitivity of tumor
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Variable expression of metabolizing enzymes
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Molecular targeting
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Pharmacokinetic determinants – AUC dosing
Drug interactions
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20-30% of interactions are caused by drugs
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Clinically relevant in up to 80% of elderly
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Complex pharmacological profile
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Narrow therapeutic window, Steep dose-toxicity curve
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PK and PD inter-patient variability
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Failure to recognize leads to over dosing or under dosing
Drug interactions
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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)
Drug interactions
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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
Drug interactions
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Pharmacodynamic
Cisplatin with gemcitabine
Cisplatin with topotecan
5FU with Leucovorin
Platelet sparing effect of Carboplatin with Taxol
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OTC medications
St. John’s wart – potent inducer - avoid with CPT-11
Prediction of drug response
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Selection of drugs based on previous trials
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Human tumor xenograft studies
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Biochemical tests – asparaginase, DHFR
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Molecular targeting – TKIs
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EGFR targeted medications
Combination therapy
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Improved response
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Decrease resistance (p-glycoprotein, MDR phenotypes)
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Non-overlapping toxicity
Classes of drugs
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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
Classes of drugs
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Cytokines
IL-2, Interferons
Immune modulators
Levamisole, BCG
Differentiation inducers
Retinoids
Glucocorticoids
immunosuppressive, lympholytic
L-asparaginase
Depletes asparagine
Classes of drugs
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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)
New targeted therapies
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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)