Anticancer drugs 2024.pdf

Anticancer Drugs Cytotoxic Drugs Antineoplastic Agents Dr. Khawla Dhamen 1  Principles of Cancer Chemotherapy üCancer chemotherapy struggles to cause a lethal cytotoxic event or apoptosis in the cancer cells that can arrest a tumor’s progression. üThe attack is...

Anticancer Drugs Cytotoxic Drugs Antineoplastic Agents Dr. Khawla Dhamen 1  Principles of Cancer Chemotherapy üCancer chemotherapy struggles to cause a lethal cytotoxic event or apoptosis in the cancer cells that can arrest a tumor’s progression. üThe attack is generally directed toward DNA or against metabolic sites essential to cell replication. Ø for example, the availability of purines and pyrimidines, which are the building blocks for DNA or RNA synthesis. üUnfortunately, most currently available anticancer drugs do not specifically recognize neoplastic cells but, rather, affect all kinds of proliferating cells, both normal and abnormal. 2  Cancer Treatment Strategies qGoals of treatment: The ultimate goal of chemotherapy is a cure (that is, long-term, disease-free survival). A true cure requires the eradication of every neoplastic cell. If a cure is not attainable, then the goal becomes control of the disease (stop the cancer from enlarging and spreading) to extend survival and maintain the best quality of life. 3 qThe neoplastic cell burden is initially reduced (debulked), either by surgery and/or radiation, followed by chemotherapy, immunotherapy, therapy using biological modifiers, or a combination of these treatment modalities. Palliation: alleviation of symptoms and avoidance of life-threatening toxicity. In advanced stages of cancer, the likelihood of controlling the cancer is far from reality. 4  Treatment options of cancer 1. Surgery: before 1955 2.Radiotherapy: 1955~1965 3. Chemotherapy: after 1965 4. Immunotherapy 5. Gene therapy 5  Indications for Treatment Chemotherapy is sometimes used when neoplasms are disseminated and are not amenable to surgery. qAdjuvant Chemotherapy: Ø Chemotherapy may also be used as a supplemental treatment to attack micrometastases following surgery and radiation treatment. qNeoadjuvant Chemotherapy: Ø Chemotherapy is given before the surgical procedure in an attempt to shrink the cancer. qMaintenance Chemotherapy Ø Chemotherapy is given in lower doses to assist in prolonging remission. 6  Tumor susceptibility and the growth cycle Rapidly dividing cells are generally more sensitive to chemotherapy, whereas slowly proliferating cells are less sensitive to chemotherapy. In general, nondividing cells (those in the G0 phase) usually survive the toxic effects of many of these agents. Cell cycle specificity of drugs: Both normal cells and tumor cells go through growth cycles , the number of cells that are in various stages of the cycle may differ in normal and neoplastic tissues. Cell Cycle Specific: Chemotherapeutic agents that are effective only against replicating cells (that is, those cells that are dividing). Cell Cycle Nonspecific : The nonspecific drugs, although having generally more toxicity in cycling cells, are also useful against tumors that have a low percentage of replicating cells.7 8 qTumor growth rate: The growth rate of most solid tumors in vivo is initially rapid, but the growth rate usually decreases as the tumor size increases. This is due to the unavailability of nutrients and oxygen caused by inadequate vascularization and lack of blood circulation. Tumor burden can be reduced through surgery and radiation. qTreatment regimens and scheduling Drug dosages are usually calculated based on body surface area, to tailor the medications to each patient. 9 q Log kill phenomenon: Destruction of cancer cells by chemotherapeutic agents follows first-order kinetics (that is, a given dose of drug destroys a constant fraction of cells). log kill is used to describe this phenomenon. For most bacterial infections, a 5-log (100,000- fold) reduction in the number of microorganisms results in a cure, because the immune system can destroy the remaining bacterial cells. Tumor cells are not as readily eliminated, and additional treatment is required to totally eradicate the leukemic cell population. 10 qPharmacologic sanctuaries: Leukemic or other tumor cells find sanctuary in tissues such as the central nervous system (CNS), where transport limitations prevent certain chemotherapeutic agents from entering. Patients may require irradiation of the craniospinal axis or intrathecal administration of drugs to eliminate the leukemic cells at that site. Drugs may be unable to penetrate certain areas of solid tumors. qTreatment protocols: Combination-drug chemotherapy is more successful than single-drug treatment in most of the cancers for which chemotherapy is effective. 11 q Combinations of Drugs: Cytotoxic agents with qualitatively different toxicities, and with different molecular sites and mechanisms of action, are usually combined at full doses. This results in higher response rates, due to additive and/or potentiated cytotoxic effects, and nonoverlapping host toxicities. Agents with similar dose-limiting toxicities, such as myelosuppression, nephrotoxicity, or cardiotoxicity, can be combined safely only by reducing the doses of each. q Advantages of drug combinations: 1) Provide maximal cell killing within the range of tolerated toxicity, 2) Effective against a broader range of cell lines in the heterogeneous tumor population. 3) May delay or prevent the development of resistant cell lines.12 qTreatment Protocols: Many cancer treatment protocols have been developed, and each one applies to a particular neoplastic state. Therapy is scheduled intermittently (approximately 21 days apart) to allow recovery or rescue of the patient’s immune system, which is also affected by the chemotherapeutic agents, thus reducing the risk of serious infection. 13 14 qProblems associated with chemotherapy Cancer drugs are toxins that present a lethal threat to the cells. Cells have evolved elaborate defense mechanisms to protect themselves from chemical toxins, including chemotherapeutic agents. q Resistance: Some neoplastic cells (for example, melanoma) are inherently resistant to most anticancer drugs. Other tumor types may acquire resistance to the cytotoxic effects of a medication by mutating, particularly after prolonged administration of suboptimal drug doses. 15 ü The development of drug resistance is minimized by short- term, intensive, intermittent therapy with combinations of drugs. Drug combinations are also effective against a broader range of resistant cells in the tumor population. q Multidrug resistance: Stepwise selection of an amplified gene that codes for a transmembrane protein (P-glycoprotein for “permeability” glycoprotein) is responsible for multidrug resistance. This resistance is due to adenosine triphosphate– dependent pumping of drugs out of the cell in the presence of P- glycoprotein. Cross-resistance following the use of structurally unrelated agents also occurs. For example, cells that are resistant to the cytotoxic effects of the Vinca alkaloids are also resistant to dactinomycin and to the anthracycline antibiotics, as well as to colchicine, and vice versa. 16 Drug Resistance 17 q Toxicity: Therapy aimed at killing rapidly dividing cancer cells also affects normal cells undergoing rapid proliferation (for example, cells of the buccal mucosa, bone marrow, gastrointestinal [GI] mucosa, and hair follicles q Common adverse effects: Most chemotherapeutic agents have a narrow therapeutic index. ü Severe vomiting, and stomatitis. ü Bone marrow suppression. ü Alopecia. Vomiting is often controlled by administration of antiemetic drugs. Some toxicities, such as myelosuppression that predisposes to infection, are common to many chemotherapeutic agents. ü Other adverse reactions are confined to specific agents, such as bladder toxicity with cyclophosphamide, cardiotoxicity with doxorubicin, and pulmonary fibrosis with bleomycin. 18 ü The duration of the side effects varies: Alopecia is transient, but the cardiac, pulmonary, and bladder toxicities can be irreversible. q Minimizing adverse effects: Ø Some toxic reactions may be improved by interventions: Perfusing the tumor locally (for example, a sarcoma of the arm). Removing some of the patient’s marrow before intensive treatment and then reimplanting. Promoting intensive diuresis to prevent bladder toxicities. The megaloblastic anemia that occurs with methotrexate can be effectively counteracted by administering folinic acid (leucovorin). q Treatment-induced tumors: Because most antineoplastic agents are mutagens, neoplasms (for example, acute nonlymphocytic leukemia) may arise 10 or more years after the original cancer was cured. ü Treatment-induced neoplasms are especially a problem after therapy with alkylating agents. ü Most tumors that develop from cancer chemotherapeutic agents respond well to treatment strategies. 19  13.ANTI CANCER DRUG CLASSIFICATION 20 21  Mechanism of Anticancer Drugs Alkylating agents and related compounds, act by forming covalent bonds with DNA and thus impeding replication. Antimetabolites, block or subvert one or more of the metabolic pathways involved in DNA synthesis. Cytotoxic antibiotics are substances of microbial origin that prevent mammalian cell division. Plant derivatives (vinca alkaloids, taxanes, campothecins) -most of these specifically affect microtubule function and hence the formation of the mitotic spindle. Hormones, of which the most important are steroids, namely glucocorticoids, estrogens, and androgens, as well as drugs that suppress hormone secretion or 22 antagonize hormone action.  Antimetabolites : Folate Antagonist Methotrexate Ø Methotrexate potently inhibits Dihydrofolate reductase (DHFR). Ø This leads to decreased production of compounds adenine, guanine and thymidine and the amino acids methionine and serine Ødepletion of thymidine. Ø Finally depressed DNA, RNA, and protein synthesis and, ultimately, to cell death. FH2 = dihydrofolate; FH4 = tetrahydrofolate; dTMP = deoxythymidine monophosphate; dUMP = deoxyuridine mono phosphate. Purine antagonist: 6-mercaptopurine Ø 6-Mercaptopurine penetrates target cells and is converted to the nucleotide analog. Ø This leads to inhibiting the first step of de novo purine-ring biosynthesis Ø This results in non- functional RNA and DNA. 24  Pyrimidine Antagonist: 5-Fluorouracil (Analogue of Uracil) Ø 5-Fluorouracil Competes with deoxyuridine monophosphate for thymidylate synthase and reduces the thymidine. Ø DNA synthesis decreases due to a lack of thymidine, leading to imbalanced cell growth. 5-FU = 5-fluorouracil; 5-FUR = 5-fluorouridine; 5-FUMP = 5-fluorouridine monophosphate; 5-FUDP = 5-fluorouridine diphosphate; 5-FUTP = 5-fluorouridine triphosphate; dUMP = deoxyuridine monophosphate; dTMP = deoxythymidine monophosphate. 5-FdUMP = 5-fluorodeoxyuridine monophosphate. 25 26 Antimetabolites: Gemcitabine Ø Gemcitabine inhibits DNA synthesis by being incorporated into sites in the growing strand that ordinarily would contain cytosine. Ø Gemcitabine diphosphate inhibits ribonucleotide reductase, which is responsible for the generation of deoxynucleoside triphosphates required for DNA synthesis. Antibiotics: Doxorubicin and Daunorubicin Ø Doxorubicin and daunorubicin Øbind to the sugar-phosphate backbone of DNA. This causes local uncoiling. Which leads to blocks DNA & RNA synthesis and catalyzed breakage of supercoiled DNA strands, causing irreversible breaks. Ø Catalyzes the reduction of free radicals. These in turn reduce molecular O2, producing superoxide ions and hydrogen peroxide, which mediate single-strand scission of DNA. 28 Antibiotics: Bleomycin ØA DNA-bleomycin-Fe2+ complex appears to undergo oxidation to bleomycin-Fe3+. ØThe liberated electrons react with oxygen to form superoxide or hydroxyl radicals, which in turn attack the phosphodiester bonds of DNA, resulting in strand breakage and chromosomal abnormalities. 29 Alkylating Agents: Mechlorethamine Ø Mechlorethamine is alkylates the N7 nitrogen of a guanine residue in one or both strands of a DNA molecule. This alkylation leads to cross-linkages between guanine residues in the DNA chains and/or depurination, thus facilitating DNA strand breakage. Ø Alkylation can also cause miscoding mutations. 30 31 Plant Derivatives: Vinca Alkaloids Vincristine and Vinblastine 32 Taxanes: Paclitaxel 33 Hormones : Estrogens In Prostatic Cancer ØFlutamide, nilutamide and bicalutamide are synthetic, nonsteroidal antiandrogens used in the treatment of prostate cancer. ØEstrogens, such as ethinyl estradiol or diethylstilbestrol, have been used in the treatment of prostatic cancer. ØHowever, they have been largely replaced by the GnRH analogs because of fewer adverse effects (Leuprolide and Goserelin). ØEstrogens inhibit the growth of prostatic tissue by blocking the production of LH, thereby decreasing the synthesis of androgens in the testis. 34 Mechanism of Action of Antiestrogen 35 Summary of Toxicity of Chemotherapeutic Agents 36