[04.07] Anti-Neoplastic Drugs (TG14-CG07) (V2) - Margaret Manuel.pdf

An -Neoplas c Drugs Module 04: Basic Pathologies II Maria Yña Eluisia T. Pereyra, RPh, MD, MBA | October 05, 2023 B. CELL CYCLE TABLE OF CONTENTS I. CANCER CHEMOTHERAPY................................................................. 1 A. LOG-KILL HYPOTHESIS............................................

An -Neoplas c Drugs Module 04: Basic Pathologies II Maria Yña Eluisia T. Pereyra, RPh, MD, MBA | October 05, 2023 B. CELL CYCLE TABLE OF CONTENTS I. CANCER CHEMOTHERAPY................................................................. 1 A. LOG-KILL HYPOTHESIS.................................................................. 1 B. CELL CYCLE................................................................................... 1 II. CANCER TREATMENT MODALITIES................................................... 2 A. PRIMARY INDUCTION CHEMOTHERAPY...................................... 2 B. NEOADJUVANT CHEMOTHERAPY................................................. 2 C. ADJUVANT CHEMOTHERAPY........................................................ 2 D. RESCUE THERAPY......................................................................... 2 III. CLASSIFICATIONS OF CHEMOTHERAPEUTIC DRUGS.........................2 A. ALKYLATING AGENTS....................................................................2 B. ANTIMETABOLITES....................................................................... 3 C. NATURAL PRODUCT ANTICANCER DRUGS................................... 4 D. ANTITUMOR ANTIBIOTICS........................................................... 5 E. MISCELLANEOUS ANTICANCER AGENTS...................................... 6 F. HORMONAL ANTICANCER AGENTS.............................................. 7 IV. SUMMARY OF SIDE EFFECTS OF ANTICANCER AGENTS.................... 9 QUESTIONS......................................................................................... 9 ANSWER KEY....................................................................................... 9 RATIONALE.......................................................................................... 9 LEARNING OBJECTIVES 1. To explain basic concepts in the use of an cancer drugs 2. To discuss the pharmacology of some an cancer drug I. CANCER CHEMOTHERAPY Figure 2. Cell cycle ● Mitosis (PMAT) ○ Prophase, metaphase, anaphase, telophase ○ Would then proceed to G1 phase ● G1 phase ○ Synthesis of cellular components needed for DNA synthesis ● S phase ○ Replica on of DNA genome/actual DNA synthesis ● G2 phase ○ Prepares for another cycle of mitosis and the cycle goes on ● G0 phase ○ Quiescent or dormant phase of cells ○ Malignant cells do not have G0 phase ▸ They bypass this phase and con nue on replica ng CELL CYCLE NONSPECIFIC DRUGS Figure 1. An -cancer drugs ● Divided into groups depending on mechanisms of ac on ○ Most act on DNA ▸ Main problem: cancer cells replicate so fast so DNA inhibitors are used to stop their replica on ● Alkyla ng agents ○ Like an metabolites ▸ Mimickers of purines and pyrimidines – Purines: Adenine, Guanine – Pyrimidines: Cytosine, Thymine, Uracil ○ Bind to the DNA bases but do not look like DNA ○ Difference between alkyla ng agents and an metabolites ▸ Alkyla ng agents don’t (chemically) look like an metabolites ● Act on tumor stem cells when they are traversing the cell cycle and when they are in the res ng phase (G0 phase) CELL CYCLE SPECIFIC DRUGS ● Act selec vely on tumor stem cells when they are traversing the cell cycle, and not when they are in the G0 phase A. LOG-KILL HYPOTHESIS ● An cancer drugs kill a fixed propor on of a tumor cell popula on, not a fixed number of tumor cells ○ Like a first rate reac on ● One ra onale for drug combina ons ○ A certain por on of an cancer drugs kills a certain type of an cancer agent and other por ons can kill other types Figure 3. Drugs ac ng on different cell cycle phases YL6:04.07 TG14: Acuña, Antonio, Ballelos, Carreon, Diño, Go, Lim, Liwanag, Manuel, Meneses CG07: Araneta, Cuanang, Dela Cruz, Gue, Jacob, King, Mercado, Obias, Orlina, San ago, Yap 1 Table 1. Drugs ac ng on different cell cycle phases Phase G0 phase (CCNS) S phase Drugs ● ● ● ● ● Cell cycle nonspecific drugs Alkyla ng agents An tumor an bio cs (Doxorubicin) Nitrosoureas (Lomus ne, Carmus ne) Cispla n (pla num deriva ves) ● ● ● ● ● ● An -metabolites (look like DNA) Clue: drug names related to purines & pyrimidines Cytarabine 6-mercaptopurine 6-thioguanine Methotrexate: inhibits folic acid synthesis ○ Folic acid has a vital role in DNA synthesis ○ Therefore, it indirectly inhibits DNA synthesis ● Hydroxyurea ● Etoposide G2 phase ● Bleomycin M phase ● ● ● ● Commonly seen in plants Vinblas ne (vinca alkaloid) Vincris ne (vinca alkaloid) Paclitaxel Table 2. An -cancer agents, their toxic effects and their rescue drug An -Cancer Agent Rescue Drug Methotrexate ↓ Folic acid levels → Hepatotoxicity Cyclophosphamide Hemorrhagic cys s Doxorubicin Dilated cardiomyopathy (an tumor an bio c and heart failure like Dac nomycin) Cispla n Nephrotoxicity and (pla num deriva ve) acous c toxicity Leucovorin/ Folinic Acid Mesna Dexrazoxane Amifos ne Ac ve Recall Box 1. What is the only G2 phase specific drug? 2. T/F: An cancer drugs mostly act on DNA. Answers: 1 Bleomycin, 2T Ra onale: 2T: Cancer cells replicate so fast so DNA inhibitors are used to stop their replica on. III. CLASSIFICATIONS OF CHEMOTHERAPEUTIC DRUGS A. ALKYLATING AGENTS Take Note! ● Bleomycin is the only G2 phase-specific drug ● Doc does not expect us to memorize the kinds of cancers that these drugs treat, unless they are really specific to that kind of cancer ○ Methotrexate: used for choriocarcinoma, H mole ● In terms of mechanisms, drugs are grouped (e.g., an metabolites, alkyla ng agents, an tumor an bio cs) ○ Would always have something to do with inhibi ng DNA II. CANCER TREATMENT MODALITIES ● General MOA: bind to DNA bases to halt DNA replica on ● Cell cycle non-specific CYCLOPHOSPHAMIDE Table 3. Cyclophosphamide Trait ● Drug therapy is administered as the primary treatment ● Only chemotherapy will be done (no surgery, no radia on) ○ E.g., leukemia pa ents Drug Class Alkyla ng agent MOA ● Forms DNA cross-links, resul ng in inhibi on of DNA synthesis and func on ● Cell cycle non-specific Clinical Use ● Non-hodgkin's lymphoma, breast cancer, ovarian cancer, neuroblastoma, chronic lymphocy c leukemia Toxici es ● Bone marrow suppression, hemorrhagic cys hepatotoxicity, alopecia, SIADH, cardiac dysfunc on, pulmonary toxicity Notes ● Rescue therapy: Mesna ● Acrolein: metabolite causing hemorrhagic cys B. NEOADJUVANT CHEMOTHERAPY ● Use of chemotherapy in pa ents with localized cancer before performing local therapy (surgery) ● Done to shrink tumor first and decrease blood supply for easier debulking of tumor ● Goal: to render the local therapy more effec ve ○ For tumor debulking Descrip on Similar Drugs Chlorambucil A. PRIMARY INDUCTION CHEMOTHERAPY D. RESCUE THERAPY ● Allevia on of toxic effects by giving rescue drugs An -Neoplas c Drugs s, s CISPLATIN C. ADJUVANT CHEMOTHERAPY ● Chemotherapy is done a er the local treatment (e.g., a er surgery or radia on) ○ For cancers in stages that have grown too large ▸ E.g., breast cancer Stage IIIC or IV, where the cancer is too big – Cannot simply perform mastectomy because of the numerous lymph nodes affected ▸ Neoadjuvant therapy is thus applied first, usually for 6 sessions ▸ Once the cancer has go en smaller, surgery can be performed ▸ A er surgery, radiotherapy is done ▸ A er radiotherapy, adjuvant chemotherapy via IV – Or orally (if lower stages of breast cancer) ▪ Drugs used: Tamoxifen or Omeprazole ● Reduces the risk of local and synthe c recurrence and to improve disease-free and overall survival YL6:04.07 Toxic Effect Table 4. Cispla n Trait Descrip on Similar Drugs Carbopla n, Oxalipla n Drug Class Alkyla ng Agent, Pla num-based MOA ● Forms DNA cross-links, resul ng in inhibi on of DNA synthesis and func on ● Cell cycle non-specific Clinical Use ● Tes cular cancer, ovarian cancer, bladder cancer, lung cancer, advanced colon cancer (Oxalipla n) Toxici es ● Nausea, vomi ng, nephrotoxicity, neurotoxicity (peripheral neuri s, acous c nerve damage) Notes ● Rescue therapy: Amifos ne ● Decrease nephrotoxicity by administering mannitol with forced hydra on 2 PROCARBAZINE Table 5. Procarbazine CARMUSTINE Table 8. Carmus ne Trait Descrip on Trait Descrip on Drug Class Alkyla ng agent Similar Drugs Lomus ne MOA ● Forms hydrogen peroxide (oxygen-free radical that kills cells), which generates free radicals that cause DNA strand scission ● Cell cycle non-specific Drug Class Alkyla ng agent (nitrosourea) MOA ● Forms DNA cross-links, resul ng in inhibi on of DNA synthesis and func on ● Cell cycle non-specific Clinical Use ● Brain tumors, melanoma, skin cancer Toxici es ● CNS toxicity (dizziness, ataxia), nausea and vomi ng, bone marrow suppression, skin flushing Notes ● Highly lipophilic, allowing ease of passage through blood brain barrier into the CNS Clinical Use ● Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, brain tumors Toxici es ● Bone marrow suppression, pulmonary toxicity, hemolysis, neurotoxicity, Disulfiram-like reac on ● Leukemogenic (induces leukemia) Notes ● Similar ac on with Dacarbazine ● Disulfiram is used as a drug indicated for chronic alcoholics and causes “hangover-like effect” to discourage individuals to drink more alcohol B. ANTIMETABOLITES ● General MOA: purine and pyrimidine analogues that mimic DNA bases to prevent DNA replica on DACARBAZINE Table 6. Dacarbazine METHOTREXATE Table 9. Methotrexate Trait Descrip on Drug Class Alkyla ng agent MOA ● Forms hydrogen peroxide (oxygen-free radical that kills cells), which generates free radicals that cause DNA strand scission ● Cell cycle non-specific Clinical Use ● Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, brain tumors Toxici es ● Alopecia, skin rash, gastrointes nal distress, bone marrow suppression, phototoxicity, flu-like syndrome Notes ● Non-leukemogenic unlike Procarbazine ● Disulfiram is used as a drug indicated for chronic alcoholics and causes “hangover-like effect” to discourage individuals to drink more alcohol BUSULFAN Table 7. Busulfan Trait Trait Descrip on Drug Class An metabolite, Disease-Modifying An -Rheuma c Drug MOA ● Inhibits dihydrofolate reductase ● Decreases synthesis of thymidylate, amino acids, purine nucleo des ● Cell cycle specific Clinical Use ● Choriocarcinoma (hyda diform mole), acute leukemias, non-Hodgkin’s lymphoma, primary CNS lymphoma, breast cancer, head and neck cancer, bladder cancer, rheumatoid arthri s, psoriasis, ectopic pregnancy Toxici es ● Bone marrow suppression, pulmonary infiltrates and fibrosis, mucosi s, crystalluria, hepatotoxic Notes ● Not really a mimicker of DNA bases but focuses its ac on on folic acid pathway ● Rescue therapy: Leucovorin (folinic acid) Descrip on Drug Class Alkyla ng agent MOA ● Forms DNA cross-links, resul ng in inhibi on of DNA synthesis and func on ● Cell cycle non-specific Clinical Use ● Chronic myelogenous leukemia Toxici es ● Pulmonary fibrosis (comparable to pa ent smoking for 30-40 pack years), adrenal insufficiency, skin pigmenta on Notes ● Spares the bone marrow (“marrow-sparing”) Figure 4. Folic acid synthesis ● p-Aminobenzoic acid (PABA) is converted to Dihydrofolate ○ Enzyme: Dihydropteroate synthase ○ An bio c: Sulfonamides (compete with PABA) ● Dihydrofolate is converted to Tetrahydrofolate ○ Enzyme: Dihydrofolate reductase ○ An bio c: Trimethoprim ● Tetrahydrofolate is the primary precursor of folic acid ● Both Methotrexate and Trimethoprim are dihydrofolate reductase inhibitors ○ Capable of inhibi ng folic acid, an important precursor of purines ○ DNA synthesis is thus inhibited YL6:04.07 An -Neoplas c Drugs 3 6-MERCAPTOPURINE Table 10. 6-Mercaptopurine GEMCITABINE Table 13. Gemcitabine Trait Descrip on Trait Descrip on Similar Drugs 6-Thioguanine, Fludarabine, Cladribine Drug Class An metabolite (pyrimidine) Drug Class An metabolite (purine) MOA MOA ● Inhibits de novo purine nucleo de synthesis ● Ac vated by HGPRT ● Cell cycle specific ● Inhibits DNA synthesis and repair ● Inhibits ribonucleo de reductase with reduced forma on of dNTPs ● Cell cycle specific Clinical Use ● Acute leukemias (AML, ALL), chronic myelogenous leukemia Clinical Use Toxici es ● Bone marrow suppression, hepatotoxicity (cholestasis, jaundice, necrosis) ● Pancrea c cancer ○ One of the most aggressive cancers ○ Usually < 1 year life span when detected ● Non-small cell lung cancer, bladder cancer, Non-Hodgkin’s lymphoma Notes ● 6-MP metabolism is inhibited by Allopurinol and Febuxostat Toxici es ● Bone marrow suppression, neutropenia, pulmonary toxicity C. NATURAL PRODUCT ANTICANCER DRUGS Take Note! ● Any purine deriva ve should not be given with an -uric acid or hypouricemic agents (e.g., Allopurinol and Febuxostat) ○ Allopurinol and Febuxostat inhibit the conversion of purines to xanthine, hypoxanthine, and eventually to uric acid ○ This increases the level of purines → significant bone marrow suppression ● Called natural because they came from plants ● Although the ones used today are synthe c, they s ll came from plants VINCRISTINE Table 14. Vincris ne Trait 5-FLUOROURACIL Table 11. 5-Fluorouracil Trait An metabolite (pyrimidine) MOA ● Inhibits thymidylate synthase ○ Leads to no thymine produc on ● Causes thymineless death of cells ● Cell cycle specific Clinical Use Toxici es Drug Class Vinca alkaloid MOA ● Prevents microtubule assembly ○ Recall: microtubules separate cells & DNA ● Causes cell arrest at metaphase ● Cell cycle specific ○ Inhibits cell cycle replica on Clinical Use ● Acute leukemias, lymphomas, Wilms tumor, neuroblastoma Toxici es ● Areflexia, peripheral neuri s, paraly c ileus Notes ● Acts primarily in M phase of the cancer cell cycle Descrip on Drug Class ● Bladder cancer, breast cancer, colorectal cancer, anal cancer, head and neck cancer, liver cancer, ovarian cancer, skin cancer (basal cell cancer, ac nic keratoses) Descrip on VINBLASTINE ● Bone marrow suppression, gastrointes nal irrita on, alopecia CYTARABINE Table 12. Cytarabine Trait Descrip on Drug Class An metabolite (pyrimidine) MOA ● Inhibits DNA synthesis and repair ● Inhibits ribonucleo de reductase with reduced forma on of dNTPs ● Cell cycle specific Clinical Use ● Acute leukemias (AML, ALL), CML in blast crisis Toxici es ● Gastrointes nal irrita on, bone marrow suppression, neurotoxicity (cerebellar dysfunc on, peripheral neuri s) Notes ● Most specific for the S phase of the cell cycle YL6:04.07 An -Neoplas c Drugs Figure 5. Madagascar periwinkle (Chichirica) Table 15. Vinblas ne Trait Descrip on Drug Class Vinca alkaloid MOA ● Prevents microtubule assembly ● Causes cell arrest at metaphase ● Cell cycle specific; inhibits cell cycle replica on Clinical Use ● Lymphomas, neuroblastoma, tes cular carcinoma, Kaposi’s sarcoma Toxici es ● Bone marrow suppression, alopecia, GI distress Notes ● Acts primarily in M phase of the cancer cell cycle ● Causes more bone marrow suppression than vincris ne 4 ETOPOSIDE TAXANES ● Podophyllotoxin also known as Mayapples ● DNA gyrase is inhibited by one group of an bio cs: fluoroquinolones (nucleic acid synthesis inhibitors) ● Recall: DNA gyrase removes supercoiling of DNA Table 18. Paclitaxel Trait Descrip on Similar Drugs Docetaxel Drug Class Taxane MOA ● Interferes with mito c spindle ● Prevents microtubule disassembly into tubulin monomers ● Cell cycle specific Clinical Use ● Advanced breast and ovarian cancers Toxici es ● Paclitaxel: neutropenia, thrombocytopenia, peripheral neuropathy, hypersensi vity ● Docetaxel: neurotoxicity, bone marrow suppression Figure 6. Mayapple plant Table 16. Etoposide Trait Descrip on Similar Drugs Teniposide Drug Class Podophyllotoxin MOA ● Inhibits DNA topoisomerase II (DNA GYRASE) ● Inhibits mitochondrial electron transport ● Cell cycle specific Clinical Use ● Lung cancer, prostate cancer, tes cular cancer, Non-Hodgkin’s lymphoma, gastric cancer Toxici es ● Bone marrow suppression, alopecia, GI distress Figure 8. Pacific Yew (Taxane plant deriva ve) Take Note! ● Vinca alkaloids inhibit microtubule assembly ● Taxanes inhibit microtubule disassembly TOPOTECAN SUMMARY Figure 7. Camptothecin (small-durian like) Table 17. Topotecan Trait Descrip on Similar Drugs Irinotecan Drug Class Camptothecin MOA ● Inhibits DNA topoisomerase I ● Cell cycle specific Clinical Use ● Topotecan: advanced ovarian cancer (2 line), small cell lung cancer ● Irinotecan: metasta c colorectal cancer Toxici es ● Bone marrow suppression, diarrhea Figure 9. Deriva ve summary of natural product an cancer drugs Take Note! nd ● Opium poppy and Hemp in the summary are not discussed in this lecture D. ANTITUMOR ANTIBIOTICS ● “-rubicin” or “-mycin” ending drugs DOXORUBICIN ● MoA is similar to alkyla ng agents YL6:04.07 An -Neoplas c Drugs 5 Table 19. Doxorubicin E. MISCELLANEOUS ANTICANCER AGENTS Trait Descrip on Similar Drugs Daunorubicin, Idarubicin, Epirubicin, Mitoxantrone Drug Class Anthracycline MOA ● ● ● ● Clinical Use Toxici es Notes Intercalates between base pairs Inhibits topoisomerase II Generates free radicals Cell cycle non-specific ● Hodgkin’s lymphoma, breast cancer, endometrial cancer, lung cancer, ovarian cancer, acute leukemias (daunorubicin, idarubicin for AML) ● Alopecia, nausea, vomi ng, dilated cardiomyopathy, conges ve heart failure Take Note! ● Remember the receptors they interact with ● Dr. Pereyra said she doesn’t expect us to remember all names but to be familiar with “last names” or similar suffixes (e.g., “- nib”) IMATINIB Table 22. Ima nib Trait Similar Drugs Dasa nib, Nilo nib Drug Class Tyrosine Kinase Inhibitors MOA ● Inhibits tyrosine kinase ac vity of the protein product of bcr-abl oncogene in CML ● Inhibits c-kit tyrosine kinase in GIST Clinical Use ● Chronic myelogenous leukemia, Gastrointes nal stromal tumor (GSIT) Toxici es ● Diarrhea, myalgia, fluid reten on, conges ve heart failure, drug interac ons Notes ● Interac ons with other drugs that depend on or affect the cytochrome P450 system (CYP450 inducer) ● Can lower down blood levels of some drugs if Ima nib is given concomitantly ● Rescue therapy: Dexrazoxane Nice to Know! ● Doxorubicin administra on is stopped when toxicity occurs (e.g., ejec on frac on lowers on 2D echo) ● Other an cancer agents will be used but Doxorubicin can be readministered if the pa ent’s heart recovers ● Doxorubicin and other an cancer therapies’ toxici es are reversible ● Unlike with alcoholic dilated cardiomyopathy, alcohol makes the toxicity irreversible Descrip on BLEOMYCIN Table 20. Bleomycin TRASTUZUMAB Table 23. Trastuzumab Trait Descrip on Drug Class An tumor an bio c MOA ● Generates free radicals, which cause DNA strand breaks ● Intercalates with DNA ● Cell cycle specific Trait Descrip on Drug Class Monoclonal an body MOA ● Acts against breast cancer cells that overexpress the HER-2/neu receptor for epidermal growth Clinical Use ● Metasta c breast cancer Clinical Use ● Hodgkin’s lymphoma, tes cular cancer, head and neck cancer, skin cancer Toxici es ● Nausea and vomi ng, chills, fever, headache ● Cardiotoxicity (conges ve heart failure) Toxici es ● Pneumoni s, pulmonary fibrosis, mucocutaneous reac ons (blisters, hyperkeratosis), alopecia, hypersensi vity, fever and chills Notes ● Subcutaneous injec on for metasta c breast cancer (usually for Stage IV - pallia ve treatment) ● Breast cancer Notes ● Most specific for the G2 phase of the cell cycle [Busulfan and Bleomycin]: Both B ● Both have lung toxici es → pulmonary fibrosis ACTINOMYCIN D Table 21. Ac nomycin D Trait Descrip on Drug Class An tumor an bio c MOA ● Binds to double-stranded DNA ● Inhibits DNA-dependent RNA synthesis ● Cell cycle non-specific Clinical Use ● Melanoma, Wilms tumor, rhabdomyosarcoma, choriocarcinoma, Kaposi’s sarcoma, gesta onal trophoblas c neoplasia Toxici es ● Bone marrow suppression, skin reac ons, gastrointes nal irrita on YL6:04.07 An -Neoplas c Drugs Take Note! ● In breast cancer, you can have hormone sensi ve or HER-2/neu sensi ve ● Ideally, you would want hormone sensi ve breast cancer in order to easily give hormonal therapy, such as Tamoxifen, Raloxifene, and Letrozole ● For Estrogen Receptor and Progesterone Receptor Nega ve (ERPR-) breast cancers, it is difficult to find an -cancer agents for this, in comparison to hormone sensi ve breast cancer ● Trastuzumab is effec ve if the breast cancer is HER-2/neu receptor posi ve ○ If the cancer is nega ve for HER-2/neu receptors, Trastuzumab cannot be given ○ One must find other newer monoclonal an bodies that can be given to act on the cancer ▸ There are some new exis ng drugs, but it is s ll in Stage/Phase IV clinical trials in the Philippines, thus it is not yet part of the discussion ▸ It is fortunate there are Stage/Phase IV clinical trials in the Philippines, so that pa ents can avail the drug at a lower price as part of the clinical trial 6 BEVACIZUMAB Table 24. Bevacizumab ASPARAGINASE Table 27. Asparaginase Trait Descrip on Trait Descrip on Drug Class Monoclonal an body Drug Class Substrate-deple ng enzyme MOA ● Inhibits binding of VEGF (Vascular Endothelial Growth Factor) to VEGFR (Vascular Endothelial Growth Factor Receptor) ○ Leads to inhibi on of VEGF signaling ● Inhibits tumor vascular permeability but enhances tumor blood flow and drug delivery MOA Depletes serum asparagine Clinical Use ● Acute lymphoblas c leukemia (ALL) Toxici es ● Hypersensi vity reac ons, acute pancrea leeding Notes ● Asparagine is a very important amino acid that cancer cells “eat” ● Deple ng the asparagine can help in controlling the prolifera on of cancer cells Clinical Use ● ● ● ● ● Toxici es ● Hypertension, infusion reac ons, arterial thrombosis, impaired wound healing, gastrointes nal perfora on, proteinuria Notes Metasta c colorectal cancer Breast cancer Non-small cell lung cancer Renal cancer Diabe c re nopathy ● Not only used for cancer, but also injected in the eye for diabe c re nopathy ALL TRANS-RETINOIC ACID (ATRA) Table 28. All trans-re noic acid (ATRA) Trait Vitamin A deriva ve MOA ● Allows DNA transcrip on and differen a on of immature leukemic promyelocytes into mature granulocytes ○ Differen a on therapy Clinical Use ● Acute promyelocy c leukemia (APML) Toxici es ● Re noic acid syndrome (dyspnea, fever, weight gain, peripheral edema) Notes Table 25. Rituximab Descrip on Drug Class Monoclonal an body MOA ● Binds to a surface protein in NHL (Non-Hodgkin’s lymphoma) cells (CD20 inhibitor) ● Induces complement-mediated lysis, direct cytotoxicity and induc on of apoptosis Descrip on Drug Class RITUXIMAB Trait s, Clinical Use ● Non-Hodgkin’s lymphoma (low-grade) ● Only vitamin that can cure cancer ● Treat re noic acid syndrome with dexamethasone ● Contraindicated in pregnant women ○ Facial products with ATRA, such as for pimples are also not allowed Toxici es ● Hypersensi vity reac ons ● Bone marrow suppression F. HORMONAL ANTICANCER AGENTS PREDNISONE INTERFERON-α Table 26. Interferon-α Trait Trait Descrip on Drug Class Interferon MOA ● Endogenous glycoproteins with an neoplas c, immunosuppressive and an viral ac ons Clinical Use ● Hairy cell leukemia ● Chronic myelogenous leukemia ● T-cell lymphomas Toxici es ● Alopecia, myalgia, depression, flu-like syndrome, thyroid dysfunc on, hearing loss ● Bone marrow suppression ● Neurologic dysfunc on Notes ● Contraindica ons include: ○ Autoimmune disease ○ History of cardiac arrhythmias/dysrhythmia ▸ INF-α is highly arrhythmogenic ○ Pregnancy ● Can also be used for Hepa s B and C YL6:04.07 An -Neoplas c Drugs Table 29. Prednisone Descrip on Drug Class Glucocor coid MOA ● Suppresses inflamma on and immune response ● May trigger apoptosis and work on nondividing cancer cells Clinical Use ● Chronic lymphocy c leukemia (CLL) ● Hodgkin’s lymphomas Toxici es ● Adrenal suppression ● Growth inhibi on, muscle was ng, osteoporosis, salt reten on, glucose intolerance, behavioral changes Notes ● Has a lot of u lity in trea ng pa ents when used correctly ○ Given to children who are lacking in lung surfactants ○ Given to fight cancer in adults ● Adrenal suppression occurs when an individual is given too much of this steroid 7 TAMOXIFEN Table 30. Tamoxifen LEUPROLIDE Table 32. Leuprolide Trait Descrip on Trait Descrip on Similar Drugs Toremifene Similar Drugs Gonadorelin, Nafarelin Drug Class Selec ve Estrogen Receptor Modulator (SERM) Drug Class GnRH analog MOA ● Estrogen antagonist ac ons in breast ssue and CNS ● Estrogen agonist effects in uterus, liver and bone MOA Clinical Use ● Hormone-responsive breast cancer ● Increased LH and FSH secre on with intermi ent administra on ● Reduced LH and FSH secre on with prolonged con nuous administra on Toxici es ● Hot flushes, thromboembolism (DVTs), endometrial hyperplasia, endometrial cancer Clinical Use Notes ● Prevents osteoporosis and decreases risk of atherosclerosis at the risk of causing endometrial cancer ● Need to monitor for endometrial cancer ○ Due to the agonis c effects of the drug in uterus ● Prostate cancer ● Advanced stages of breast cancer ● Hyperprolifera ve states in uterus and ovary ○ Controlled ovarian hypers mula on, endometriosis, myoma uteri ● Precocious puberty (e.g., menstrua on at 5 y/o) Toxici es ● Hot flushes, sweats, headache, osteoporosis, gynecomas a, reduced libido, decreased hematocrit, apoplexy, blindness Notes ● Must be co-administered with flutamide to prevent tumor flare-up on ini a on of treatment Take Note! ● Raloxifene ○ Same drug class as Tamoxifen ○ Advantage: has no agonis c effects in the uterus ▸ Devoid of the increased risk of developing endometrial cancer ○ Disadvantage: not as effec ve in terms of breast ssue antagonism ○ More commonly used as an agent for osteoporosis ● Tamoxifen is s ll more commonly used when trea ng breast cancer Nice to Know! ● Tamoxifen is frequently given as oral tablets ○ Free from DOH when you have breast cancer stage 3B and below ○ DOH will provide this for a minimum of 5 years Take Note! ● Give pulsa le doses of GnRH analogs ○ To induce LH and FSH produc on in anterior pituitary ○ For infer lity, problems with hypogonadism ▸ Situa ons needing s mulatory LH, FSH ● Give con nuous GnRH analog via drip or infusion ○ Cause a nega ve feedback event ○ Body detects high levels of GnRH ○ Body stops GnRH secre on ○ Reduc on of LH and FSH secre on ANASTROZOLE Table 33. Anastrozole Trait FLUTAMIDE Table 31. Flutamide Trait Descrip on Similar Drugs Bicalutamide, Nilutamide Drug Class Androgen antagonist MOA ● Compe Clinical Use ● Prostate cancer, surgical castra on (nilutamide) Toxici es ● Gynecomas a, hot flushes, impotence, hepatotoxicity Notes ● Less hepatotoxicity with bicalutamide and nilutamide ● GnRH analogs (leuprolide) must be co-administered with flutamide to prevent acute flare-up of prostate cancer Descrip on Similar Drugs Letrozole Drug Class Estrogen synthesis inhibitor MOA ● Reduces estrogen synthesis by inhibi ng aromatase enzyme ○ Recall: aromatase converts testosterone to estrogen ○ Cancer cells are sensi ve to estrogen Clinical Use ● Breast cancer ○ For menopausal women: have decreased estrogen and progesterone receptors ● Precocious puberty Toxici es ● Nausea, diarrhea, hot flushes, bone and back pain, dyspnea, peripheral edema Notes ● Effec ve against breast cancers that have become resistant to tamoxifen ve antagonist at androgen receptor Take Note! Ac ve Recall Box ● GnRH analogs ○ There are types of administra on where GnRH analogs and family can increase the ac vity of cancer cells ● Flutamide is given to inhibit the ac vity of these cancer cells ○ However, this drug is s ll specific for prostate cancer 1. T/F: GnRH analogs given in pulsa le doses decrease LH and FSH secre on. 2. What does anastrozole inhibit? Answers: 1F, 2 Aromatase, estrogen synthesis Ra onale: 1F: GnRH analogs given in pulsa le doses increase LH and FSH secre on. YL6:04.07 An -Neoplas c Drugs 8 IV. SUMMARY OF SIDE EFFECTS OF ANTICANCER AGENTS Figure 10. Chemo-tox man summarizing side effects of an cancer drugs Table 34. Summarized side effects of an cancer agents An cancer Agent Side Effect Doxorubicin ● Puffy face ● Heart: Dilated cardiomyopathy, cardiotoxicity Cispla n Carbopla n ● Ears: Ototoxicity ● Kidneys: Nephrotoxicity Bleomycin Busulfan ● Baga/Lungs: Pulmonary fibrosis Vincris ne ● Arms & legs: Peripheral neuropathy Cyclophosphamide ● Urinary bladder: Hemorrhagic cys Methotrexate 5-Fluorouracil 6-Mercaptopurine s ● Bone marrow: Myelosuppression QUICK REVIEW QUESTIONS 1. Which of the following is an alkyla ng agent? A. Bleomycin B. Prednisone C. Etoposide D. Cispla n 2. What is the rescue agent used to address the hepatotoxicity caused by Methotrexate? A. Mesna B. Dexrazoxane C. Leucovorin/Folic Acid D. Amifos ne 3. T/F: Cytarabine is an alkyla ng agent that is most specific for the S phase of the cell cycle. 4. Primary induc on chemotherapy is most commonly done in leukemia pa ents. Malignant cells can enter the G0 phase. A. Only statement 1 is true B. Only statement 2 is true C. Both statements are true D. Both statements are false 5. What an cancer drug spares the bone marrow? A. Busulfan B. Dacarbazine C. Procarbazine D. Methotrexate E. None of the above YL6:04.07 An -Neoplas c Drugs 6. Which plant deriva ves are correctly paired with the right natural product an cancer drugs? I. Vinblas ne : Madagascar Periwinkle II. Etoposide : Mayapple III. Topotecan : Pacific Yew IV. Taxane : Happy Tree A. I and II B. II and III C. III and IV D. I and IV 7. Which of the following has higher effects on bone marrow suppression? A. Vincris ne B. Vinblas ne C. Vindisteine D. AOTA 8. Which drug exerts an estrogen antagonis c ac on in breast ssue and CNS? A. Tamoxifen B. Prednisone C. Ima nib D. Leuprolide 9. Ka e is recently diagnosed with HER-2/neu receptor nega ve breast cancer. Which of the following drugs is BEST for her chemotherapy treatment? A. Prednisone B. Trastuzumab C. Flutamide D. Bleomycin E. None of the above 10. Which of the following an cancer agents is correctly matched with its corresponding side effect? A. Carbopla n: Pulmonary fibrosis B. 5-Fluorouracil: Cardiotoxicity C. Vincris ne: Peripheral neuropathy D. Bleomycin: Hemorrhagic cys s ANSWER KEY 1D, 2C, 3F, 4A, 5A, 6A, 7B, 8A, 9E, 10C RATIONALE 1. D. Cispla n. Bleomycin is an an tumor an bio c. Prednisone is a hormonal an cancer drug and lastly, Etoposide is a natural product. 2. C. Leucovorin/Folic Acid. Leucovorin/Folic Acid is the rescue agent used to address the hepatotoxicity caused by Methotrexate. 3. False. Cytarabine is an an metabolite (pyrimidine) that is most specific for the S phase of the cell cycle. 4. A. Only statement 1 is true. Malignant cells bypass the G0 phase and con nue on replica ng. 5. A. Busulfan. Unlike most an cancer drugs suppressing the bone marrow as its side effect, Busulfan is known and beneficial to be bone marrow-sparing. 6. A. I and II. Vinca alkaloids (Vincris ne and Vinblas ne) are derived from Madagascar periwinkle, Etoposide from Mayapple, Topotecan from Happy tree, and Taxanes (Paclitaxel and Docetaxel) from Pacific yew. Refer to Figure 9. 7. B. Vinblas ne. Vinblas ne causes more bone marrow suppression than vincris ne. Op on C does not exist. 8. A. Tamoxifen. Tamoxifen exerts an estrogen antagonist in breast ssue and CNS. Prednisone is a glucocor coid that suppresses inflamma on and immune response. Ima nib is a tyrosine kinase inhibitor, while leuprolide is a GnRH analog that induces LH and FSH produc on. 9. E. None of the above. Trastuzumab is indicated as an an -breast cancer drug, however it is only effec ve for HER-2/neu receptor posi ve breast cancers. Other drugs must be used in order to address Ka e’s case, however the other men oned drugs are not indicated for breast cancer. Prednisone is indicated for Chronic lymphocy c leukemia (CLL) and Hodgkin’s lymphomas. Ima nib is indicated for Chronic Myelogenous Leukemia, and Gastrointes nal Stromal Tumor (GSIT). Bleomycin is indicated for Hodgkin’s lymphoma, tes cular cancer, head and neck cancer, and skin cancer. 9 10. C. Vincris ne: Peripheral neuropathy. Recall chemo-tox man. Carbopla n and cispla n results in ototoxicity and nephrotoxicity. 5-fluorouracil, methotrexate, and 6-mercaptopurine result in myelosuppression. Bleomycin and busulfan result in pulmonary fibrosis. Doxorubicin results in cardiotoxicity, dilated cardiomyopathy, and puffy face. Cyclophosphamide results in hemorrhagic cys s. REFERENCES REQUIRED ● 📄 Pereyra, M. Y. E. T. (2023, October 05). Cancer chemotherapy. [Lecture slides]. SUPPLEMENTARY Concerns and Feedback form: h p://bit.ly/YL6CFF2027 How’s My Transing? form: h ps://bit.ly/2027YL6HMT Mid-Semester Evalua on form: h ps://bit.ly/2027YL6MidSem End-of-Semester Evalua on form: h ps://bit.ly/2027YL6EndofSem Errata Points Trackers: h ps://bit.ly/YL62027EPT YL6 TransMap: h ps://bit.ly/2027YL6TransMap YL6:04.07 An -Neoplas c Drugs 10