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 1942Louis 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. 1946Published their landmark results in the Journal of the American Medical Association. Reprinted in JAMA in 1984.

3. History 1948Sydney 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. 1950sIntroduction of combination chemotherapy

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

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

8. Goals of therapy Curative Curative Childhood leukemia Testicular Cancer Hodgkin’s disease Stage I through III Breast Cancer Palliative (slow down disease progression) 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) Surgery ( localized disease, staging, palliation, endocrine ablation, debulking) Radiation (localized disease, debulking, palliation) Radiation (localized disease, debulking, palliation) Chemotherapy Chemotherapy Immunotherapy 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 Growth Fraction Doubling time 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 undergo the same cellular processes (replication, division) Tumor cells don’t necessarily grow faster than normal cells Tumor cells don’t necessarily grow faster than normal cells Non-specific agents interfere with these processes Non-specific agents interfere with these processes Ideal chemotherapy is toxic to tumor cells but spares normal cells Ideal chemotherapy is toxic to tumor cells but spares normal cells Cell cycle specific agents – antimetabolites, Vinca alkaloids Cell cycle specific agents – antimetabolites, Vinca alkaloids Cell cycle non-specific agents – Doxorubicin, Cisplatin Cell cycle non-specific agents – Doxorubicin, Cisplatin Give the most effective therapy early in disease pricess Give the most effective therapy early in disease pricess

14. Purposes of Chemotherapy Primary – shrink or eliminate tumor Primary – shrink or eliminate tumor Neoadjuvant – make tumor more amenable to other therapies Neoadjuvant – make tumor more amenable to other therapies Adjuvant – eradicate micro metastasis Adjuvant – eradicate micro metastasis Palliation – symptom control 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 Risk of recurrence despite surgical resection Failure of chemotherapy to cure after recurrence Failure of chemotherapy to cure after recurrence Cancers most sensitive to chemotherapy in early stages Cancers most sensitive to chemotherapy in early stages Decreased probability of biochemical resistance Decreased probability of biochemical resistance Disadvantage – exposure of truly cured patients to chemotherapy Disadvantage – exposure of truly cured patients to chemotherapy Late complications – sterility, risk of secondary malignancy

16. Kinetic basis of Chemotherapy Fractional kill hypothesis Fractional kill hypothesis Tumor accumulates between cycles chemotherapy follows exponential log kill (never reaches zero) Phase specific agents – schedule dependent 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 Phase non-specific agents exert effects throughout the cell cycle dose or concentration dependent effects may have effect in resting phase Biochemical heterogeneity Biochemical heterogeneity

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

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

19. Drug interactions Pharmaceutical 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 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) EliminationNSAIDs and MTX or Cisplatin

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

22. Prediction of drug response Selection of drugs based on previous trials Selection of drugs based on previous trials Human tumor xenograft studies Human tumor xenograft studies Biochemical tests – asparaginase, DHFR Biochemical tests – asparaginase, DHFR Molecular targeting – TKIs Molecular targeting – TKIs EGFR targeted medications EGFR targeted medications

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

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

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

26. Classes of drugs Monoclonal antibodies - Unconjugated Monoclonal antibodies - Unconjugated Rituximab - (Rituxan) - lymphoma (CD20) Trastuzumab (Herceptin) - breast (her2) Alemtuzumab (Campath) – CLL (CD52) Monoclonal antibodies – congugated Monoclonal antibodies – congugated Ibritumomab (Zevalin) – Y 90 labeled Tositumomab (Bexxar) – I 131 labeled Immunotoxin Immunotoxin Gemtuzumab (Mylotarg) – AML (CD33)

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