Pharmacology of Chemotherapy agents

1. Pharmacology of Chemotherapy agents David Samuel PharmD BCOP

2. 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.

3. 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

4. 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)

5. Etiology • Knudson’s two hit theory (Rb gene) 1971 • R. White – clonality – (APC gene) 1987

8. Goals of therapy • 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

9. 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

10. 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.

11. Gompertzian growth

12. Chemotherapy considerations • 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

14. 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 > reduction in tumor size or markers and no new disease for 1 month SD – no reduction or growth Progression – 25% increase in tumor size

15. 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

16. 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

17. Determinants of response • In-vitro testing • Inherent sensitivity of tumor • Variable expression of metabolizing enzymes • Molecular targeting • Pharmacokinetic determinants – AUC dosing

18. 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

19. 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)

20. 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

21. Drug interactions • Pharmacodynamic Cisplatin with gemcitabine Cisplatin with topotecan 5FU with Leucovorin Platelet sparing effect of Carboplatin with Taxol • OTC medications St. John’s wart – potent inducer - avoid with CPT-11

22. 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

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

24. 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

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

26. 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)

27. 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)