Principles of Chemotherapy :Principles of Chemotherapy Jennifer Ribowsky, RPA-C, MS


Cancer :Cancer Cancer- disease of cell’s normal growth and differentiation; uncontrolled and abnormal differentiation and growth – express primitive cell surface antigens, chromosomal aberrations, proliferate excessively to form local tumors that compress and may invade normal tissues and metastasize or spread to distant sites Second most common cause of death in the USA 17% or so can be cured by chemotherapy


Cancer :Cancer


Cancer :Cancer


Antineoplastics :Antineoplastics Ideal antineoplastic drugs eradicate cancer cells without harming normal cells- present agents have significant toxicity b/c unlike antibiotics which deal with genetically different cells- chemo drugs have difficulty distinguishing malignant from normal cells Cancer cells divide and mutate rapidly and they develop resistance ? must use combination of agents to overcome resistance


Toxicities of Chemo :Toxicities of Chemo Bone marrow suppression Leuko/ Neutropenia, thrombocytopenia and anemia GI N/V Stomatitis Reproductive Carcinogenic Skin/ hair Neurotoxicity Urologic/ nephrotoxicity Other


Cell cycle Kinetics :Cell cycle Kinetics M phase mitosis (2%) G0 resting phase for cell differentiaton G1 phase – 40% synthesize material for DNA replication S phase – 39% DNA replication G2 synthesize material for mitosis (19%)


More info on mitosis and cell cycle :More info on mitosis and cell cycle http://www.biology.arizona.edu/Cell_bio/tutorials/cell_cycle/cells2.html http://www.biology.arizona.edu/Cell_bio/tutorials/cell_cycle/cells3.html http://www.sci.sdsu.edu/multimedia/mitosis/mitosis_gif2.html


Basics of Molecular Biology: :Basics of Molecular Biology: DNA contains hereditary information in genes ? DNA synthesis http://207.207.4.198/pub/flash/24/menu.swf Protein synthesis: During protein synthesis http://www.wisc-online.com/objects/index_tj.asp?objid=AP1302 http://207.207.4.198/pub/flash/26/transmenu_s.swf


Basic Chemotherapy Classes :Basic Chemotherapy Classes Alkylating agents Antimetabolites Plant alkaloids Biological agents (monoclonal antibodies) Growth inhibitors Enzyme inhibitors Antibiotics Hormonal agents


5 Basic Mechanisms of Action: :5 Basic Mechanisms of Action: Crosslinking DNA so it cannot separate or replicate Mimic or fill in for DNA bases causing incorporation into DNA or RNA, block enzymes in biosynthetic pathways prevents repair of DNA or terminates chain formation during DNA synthesis; stops producing purines Intercalating between base pairs of DNA disrupting codons or producing free radicals that damage DNA Biological agents Monoclonal antibodies bind to tumor cell surface receptors and prevent/interfere with growth of tumor cell Block enzymes and prevent cell growth Hormonal agents may antagonize receptors to prevent hormonally induced tumor growth


Alkylating Drugs (toxic to hematologic system) :Alkylating Drugs (toxic to hematologic system) Mechanism of action: Adds alkyl* group to bases on DNA and crosslinks DNA leads to breaks in DNA strands Mechlorethamine (nitrogen mustard) N/V and myelosuppression, vesicant if extravasated can cause tissue damage used IV in MOPP therapy for Hodgkin’s lymphoma Cyclophosphamide (Cytoxan) Toxicity – myelosuppression and hemorrhagic cystitis (see picture) , N/V and alopecia Must hydrate well (IV and PO) and Ifosfamide is similar to cyclophosphamide


Alkylating Drugs :Alkylating Drugs Phenylalanine mustard (Melphalan) Cross links DNA by binding to both strands Toxicity- myelosuppression used for multiple myeloma Nitrosureas (carmustine, lomustine, semustine) Cross BBB and cross link DNA thru alkylation used for brain tumors and other tumors, lymphomas MYELOSUPPRESSION, nephrotoxicity, acute N/V


Alkylating Drugs :Alkylating Drugs Dacarbazine which causes marked N/V in > 90% pts, flulike syndrome and myelosupression Platinum (Pt)- containing drugs- Cisplatin and carboplatin Cisplatin ? severe N/V, renal dysfunction and acoustic nerve dysfunction Carboplatin less GI and nephro but more myelosuppression Tx of many tumors solid, hematologic, Hodgkins, ovarian, bladder, testicular and GI cancers Major toxicity of alkyating agents is myelosuppression esp. WBCs and platelets Most useful alkylating agent is cyclophosphamide RECAP: Acute toxicity of alkylating chemo drugs ? N/V esp. with platinum based drugs such as cisplatin; delayed toxicities mostly myelosuppression


Antimetabolites :Antimetabolites Methotrexate – folic acid antagonist – Folic acid is IV and po forms Toxicities? oral and GI ulcerations, myelosuppression; leucovorin rescues normal cells hepatotoxicity with chronic therapy


Basics :Basics


Antimetabolites :Antimetabolites Purine antagonists ? when activated, inhibits enzymes in purine ribonucleotide synthesis, decreases amounts of guanine and may incorporate into DNA and RNA 6-mercaptopurine (po) treats leukemias; tox: GI and hepatotoxicity (dose-related); interacts with allopurinol, mild bone marrow suppression 6- thioguanine (po) – treats Acute Myelogenous Leukemia (AML); causes more myelosuppresson and Hyperuricemia


ANTIMETABOLITES Pyrimidine analogs/ antagonists (cytosine and thymine) :ANTIMETABOLITES Pyrimidine analogs/ antagonists (cytosine and thymine) 5-fluorouracil (5-FU)? undergoes metabolism and forms active metabolite which binds with thymidylate synthase needed for thymine (pyrimidine) synthesis ? no thymine; imbalance DNA and RNA synthesis and cell death major toxicities are stomatitis and esophagopharyngitis with ulceration (mucositis), bone marrow suppression Cytarabine ? for AML injectable agent that inhibits DNA polymerase and mimic cytosine, incorporated into DNA causing defective DNA and chain termination major toxicities severe myelosuppresson esp. neutrophils, N, V, and occasionally mucositis


ANTIMETABOLITE :ANTIMETABOLITE Gemzar (gemcitabine HCl) is a nucleoside analogue Blocks enzymes needed to make the building blocks of DNA Incorporates into DNA (mimic) and stops DNA synthesis ? may trigger apoptosis Adverse effects Myelosuppression (dose-limiting) anemia (must monitor CBC) Mild to moderate N/V and diarrhea Rash Fever


Mitotic Spindle :Mitotic Spindle http://micro.magnet.fsu.edu/cells/mitosisjava/mitosisjava.html Structure of cytoskeleton Segregates chromosomes during cell division Formed by microtubules Chemo drugs can cause dysfunction of spindle


Plant alkaloids :Plant alkaloids Vincristine (vinca alkaloids) Binds to tubulin and terminates microtubule (cytoskeleton) assembly? halts mitosis Used to treat lymphomas tox: alopecia and neuromuscular deficits (neuropathies) and injection site necrosis Vinblastine (vesicant) (vinca alkaloid) Treats lymphomas and other cancers Tox: LEUKOPENIA, NEUROLOGICAL, alopecia


Plant Alkaloids :Plant Alkaloids Etoposide and teniposide (podphyllotoxins) MOA: Etoposide used for testicular and certain lung cancers Major toxicities are myelosuppression and N/V Tenoposide used for ALL AE: myelosuppresson esp neutropenia, mucositis, and N/V


More Plant Alkaloids :More Plant Alkaloids Taxanes (paclitaxel, docetaxel) Microtubulin poison ? disrupts cytoskeleton formation Tox: myelosuppression, peripheral neuropathy in high doses, mucositis Topotecan and irinotecan- MOA: Topotecan: myelosuppression (all lines), N/V Irinotecan: late and severe diarrhea, N/V, alopecia and less leukopenia


Antibiotics :Antibiotics Anthracyclines: (daunorubicin and doxorubicin) MOA: intercalates with DNA causing breaks, generate DNA damaging free radicals (daunorubicin also acts asTopoisomerase II inhibitor Used for solid tumors, hematogenous cancers Toxicities: cardiotoxic at high cumulative doses (acute and late onset); myelosuppression, alopecia, stomatitis Infusion rxs in up to 10% of patients with flushing, facial swelling, SOB< back pain, hypotension Must discontinue


Antibiotics :Antibiotics Dactinomycin MOA: intercalates between DNA bases where it inhibits DNA dependent RNA polymerase (protein synthesis) Used for: pediatric sarcomas Toxicities: anorexia, N/V; later effects include alopecia, mucositis and BM suppression


Antibiotics- Bleomycin :Antibiotics- Bleomycin Bleomycin (LUNG and SKIN) MOA: reacts with Oxygen and iron to form free radicals; binds to DNA and breaks backbone of DNA chain Used for germ cell tumors of testis and ovary Toxicities: most serious is pulmonary fibrosis Cutaneous irritation, redness and ulceration; fever and chills


Hormones and miscellaneous agents :Hormones and miscellaneous agents Antiestrogens- selective estrogen receptor (ER) modulators (Tamoxifen) and newer drug, Fulvestrant (downregulates expression of ER) Use: ER positive Breast cancer treatment and prevention in high risk pts MOA: AE: hot flashes, N/V, increased TE events,?risk of endometrial cancer (monitor)


Hormones and miscellaneous agents :Hormones and miscellaneous agents GnRH releasing analogs- (leuprolide, goserelin) GnRH analogs initially stimulate FSH and LH then inhibit ? decreased testosterone (medical castration) and decreased estrogens Used for prostate cancer and metastatic breast cancer AE: Hot flashes, decreased bone mass, libido decline New drug GnRH antagonist


Hormones :Hormones Antiandrogens may be useful for prostate cancer MOA and AE: Aromatase inhibitors (inhibit aromatase, the enzyme that converts androgen to estrogen? less estrogen) Anastrozole and letrozole are used for breast cancer (po); well-tolerated


Miscellaneous :Miscellaneous Tretinoin ? Vitamin A derivative which binds to retinoic receptors and may cause terminal differentiation of leukemic cells


Immunomodulators :Immunomodulators Immunotherapy (alpha IFN and IL 2) Steps up the immune system response to killing cancer cells


Monoclonal antibodies - Several newly approved agents :Monoclonal antibodies - Several newly approved agents Rituxan (rituximab) a monoclonal antibody that binds to the CD20 antigen on B lymphocytes, and the Fc domain recruits immune effector functions to mediate B-cell lysis (NHL) HERCEPTIN (Trastuzumab) is a recombinant DNA-derived humanized monoclonal antibody that selectively binds to the extracellular domain of the human epidermal growth factor receptor 2 protein. Metastatic breast cancer in cancers that overexpress HER 2) Erbitux (cetuximab) for injection is a monoclonal antibody for metastatic colorectal cancer Bevacizumab (Avastin) binds Vascular Endothelial Growth Factor (VEGF) and prevents the interaction of VEGF to its receptors (Flt-1 and KDR) on the surface of endothelial cells. metastatic colorectal cancer


Radioimmunotherapy :Radioimmunotherapy Radioimmunotherapeutic agents (Bexxar) , Iodine 131 Tositumomab): B cell NHL Zevalin (ibritumomab tiuxetan) consists of a monoclonal antibody linked to the radioactive isotope yttrium-90.


Tyrosine Kinase Inhibitors :Tyrosine Kinase Inhibitors Tyrosine Kinase- abnormal enzymes (and receptors) which may be responsible for tumor growth, pathologic angiogenesis, metastatic progression Imatinib (Gleevec) used for chronic myeloid leukemia for blast crisis, and chronic phase after failure of interferon therapy MOA: Inhibits the abnormal protein tyrosine kinase -? inhibition of tumor cell growth Sprycel (dasatinib) is a tyrosine kinase inhibitor...similar to Gleevec.   Sutent (sunitinib)   another oral tyrosine kinase inhibitor Tarceva – inhibits kinase associated with epidermal growth factor receptor


Bone marrow recovery during chemotherapy :Bone marrow recovery during chemotherapy Growth factors for granulocytes and (macrophages) (filgrastim, pegfilgrastim) (Neupogen, Neulasta) (G-CSF) Administration Adverse effects


Anemia secondary to cancer chemotherapy :Anemia secondary to cancer chemotherapy Recombinant erythropoietin (Procrit, Epogen), 150units/kg three subcutaneously times/ week for 8 weeks adverse effects: HA, hypertension, N/ V and edema, injection site reactions Other


Chemo-induced N/V (CINV) :Chemo-induced N/V (CINV) Emetogenic Chemo regimens require pre and post chemo antiemetic regimens with multiple drugs (more in Fall during antiemetics GI lecture)


CINV :CINV