Cancer Pharmacotherapy Quiz

Lecture 8: Anticancer Drugs

• Anticancer drugs target specific areas of cell function vital to cancer cell proliferation and halting its growth.
• This lecture covers alkylating agents, antimetabolites, and mitotic inhibitors.
• The lecture is presented by Matin A. Mahmood; M.Sc. Pharmacology & Toxicology Ph.D. Pharmacology.

Hallmarks of Cancer

• Rapid uncontrolled cell proliferation
• Malignant transformation
• Resistance to apoptosis
• Inducing angiogenesis
• Invasion and metastasis
• Loss of function
• Avoiding immune destruction

Proliferation, Differentiation, Undifferentiation

• Cells have different stages: differentiated, doubling time and undifferentiated.
• Malignant transformation leads to a loss of differentiation and uncontrolled proliferation.

Cell Cycle Regulators

• Cell cycle regulators are classified as positive or negative controls.
• Positive regulators include growth factors and protein kinase receptors.
• Negative regulators include P53 and BRCA1, BRCA2.
• A diagram showing the cell cycle and checkpoints is included.

Cancer Cell Cycle Kinetics

• Some anticancer drugs (CCS) are specific for cycling cells while others (CCNS) act on both cycling and resting cells, although cycling cells are more sensitive.

• Different drugs are usually more effective when cells are in specific phases of the cell cycle.

Cancer Cell Cycle Kinetics (Diagram)

• Cell cycle (as a clock) depicting the different phases, such as G0, G1, S, G2, M, with percentages of the cell cycle spent in each phase.

Principles of Cancer Chemotherapy

• Cancer chemotherapy aims to eliminate cancer cells through cytotoxic events or apoptosis or arrest the growth of the tumor.
• The attack is targeted towards DNA and metabolic sites essential for cell replication.

Anticancer Drugs and Their Effects

• Ideally, anticancer drugs target unique aspects of malignant cells.
• Existing drugs affect all proliferating cells, both normal and abnormal.
• This characteristic of varying effects results in a steep dose-response curve for both therapeutic and toxic outcomes.
• Newer methods aim to use a patient's own immune system to target cancer cells.

Treatment Strategies

• The ultimate goal of chemotherapy is long-term, disease-free survival.
• A cure requires eliminating every neoplastic cell.
• If a cure isn't possible, controlling the disease's progression, extending survival and maintaining quality of life.
• Cancer is treated as a chronic disease, allowing for quality of life.

Overview of Treatment Strategies

• The initial neoplastic burden may be reduced with surgery, radiation, chemotherapy, immunotherapy, etc or a combination of these methods.
• In advanced stages, palliation (managing symptoms) is the goal, alongside the avoidance of life-threatening toxic effects.
• This helps improve the quality of life, though survival may not be extended.

Cancer Treatment Options

• Cancer treatment options include surgery, radiation, chemotherapy, hormonal therapy, immunotherapy, bone marrow transplantation, and palliative therapy.

Indications for Treatment

• Chemotherapy is used when neoplasms are not treatable through surgery, or for supplemental treatment of micrometastases following initial treatments.
• It can be administered prior to surgery to shrink the tumor.
• Lower doses are sometimes used to maintain remission

Treatment Protocols

• Combination chemotherapy is often more successful than single-drug treatment for cancer.
• Combining drugs with various toxicities and mechanisms of action, at full doses is usually best.
• Similar toxicities from specific drugs can be managed by adjusting dosages.

Resistance to Anticancer Drugs

• Drug resistance, a major problem in cancer chemotherapy, has several mechanisms.
• Increased DNA repair: resistance to alkylating agents and cisplatin.
• Formation of trapping agents: increased glutathione in some cancers reducing the efficacy of certain types of anticancer drugs
• Changes in target enzymes
• Decreased activation of prodrugs
• Reduced drug accumulation: The MDR1 gene, which leads to increased expression of protein-glycoprotein, can lower drug efficacy
• Different mechanisms of resistance to anticancer drugs, like increased DNA repair or the formation of trapping agents.

Adverse Effects of Anticancer Drugs

• Common adverse effects (AEs) of anticancer drugs (ACDs) include bone marrow toxicity (myelosuppression), impaired wound healing, hair loss, damage to gastrointestinal (GI) epithelium, sterility, and liver damage (hepatotoxicity).
• Some drugs cause teratogenic and carcinogenic effects

Classes of Anticancer Drugs

• Anticancer drugs are divided into several classes, including alkylating agents, antimetabolites, cytotoxic antibiotics, microtubule inhibitors, hormone antagonists, monoclonal antibodies, tyrosine kinase inhibitors, and miscellaneous agents.

Alkylating Agents

• Alkylating agents, such as nitrogen mustards (chlorambucil, cyclophosphamide), nitrosoureas (carmustine), and platinum compounds (cisplatin), work by DNA cross-linking.
• Alkylation of DNA is probably the crucial cytotoxic reaction that kills the tumor cells. Alkylating agents work even against resting cells and are thus used in combination with other anticancer drugs.
• The use of alkylating agents can result in toxic effects such as secondary malignancies.
• Different types of alkylating agents are introduced for different uses.
• Cyclophosphamide example: is the most commonly used alkylating agent, but is an activated prodrug. Its side effects include bone marrow suppression, hepatotoxicity, and alopecia; hemorrhagic cystitis may result from the byproducts ifosfamide and acetaminophen.

Cisplatin

• Cisplatin: Platinum compound, DNA cross-linking, testicular and ovarian cancers.
• General adverse events: Bone marrow depression (mild), hepatotoxicity, alopecia and nausea/vomiting.
• Specific adverse events: nephrotoxicity, sensory hearing loss, and peripheral neuropathy.

Antimetabolites

• Antimetabolites are structurally similar to normal metabolites but disrupt normal cell processes.
• Examples include methotrexate (folic acid antagonist) and 6-mercaptopurine, 5-fluorouracil (purine and pyrimidine analogues). These agents disrupt DNA and RNA synthesis.

Methotrexate (MTX)

• Mechanism of action: MTX inhibits dihydrofolate reductase, an enzyme essential for the production of tetrahydrofolic acid.

• This prevents the synthesis of purines, pyrimidines, and thymidylate.

• It works by inhibiting folate metabolism and therefore DNA synthesis.

• Therapeutic uses: MTX is used in combination with other drugs or as a low-dose single agent for specific types of cancer and certain inflammatory conditions.

• Pharmacokinetics: MTX is variably absorbed from the gastrointestinal tract, and its metabolite is less water soluble than MTX, which may lead to crystalluria. Urine alkalinization and patient hydration are important to avoid renal toxicity. Adverse effects: Bone marrow depression, hepatotoxicity, teratogenicity, megaloblastic anemia, and mucosal ulceration. Folinic acid supplementation is used to prevent megaloblastic anemia.

6-Mercaptopurine (6-MP)

• Mechanism of action: Interferes with purine nucleotide synthesis, inhibiting DNA and RNA synthesis.
• Adverse effects: Bone marrow depression, hepatotoxicity, and teratogenicity.
• Specific adverse effects: the enzyme thiopurine S-methyltransferase (TPMT) converts 6-MP into a nontoxic compound. Some patients have genetic TPMT deficiency, consequent severe adverse events (myelosuppression). Concomitant use of allopurinol (xanatine oxidase inhibitor)with this type of drug can lead to severe toxicity due to its interference with xanthine metabolism

Antibiotics (Doxorubicin)

• The cytotoxic action of antibiotics, such as doxorubicin, is often due to their interactions with DNA.
• Doxorubicin inhibits DNA and RNA synthesis.
• The main adverse effect of doxorubicin is irreversible, dose-dependent cardiotoxicity which is caused from free radical formation causing lipid peroxidation
• Other anticancer antibiotics like bleomycin and mitomycin C, also have different mechanisms and adverse effects like pulmonary fibrosis and nephrotoxicity.

Microtubule Inhibitors (Vinca Alkaloids)

• Mitotic spindle components: essential for accurate cell division
• Vinca alkaloids (vincristine, vinblastine): block the proper functioning of the mitotic spindle.
• Adverse effects: general effects such as hepatotoxicity and alopecia, and less commonly neurotoxicity.
• Paclitaxel and docetaxel: Plant-derived substances that also target microtubules. Paclitaxel was the first taxane used in chemotherapy for treating cancer. Paclitaxel and docetaxel are valuable drugs in treating various types of cancer.

Hormones and Hormone Antagonists

• Some cancers are hormone dependent (breast, prostate).
• Hormone antagonists (tamoxifen, aromatase inhibitors, antiandrogens) are used to interrupt the hormone's effect on cancer cell growth.
• Tamoxifen: Selective estrogen receptor modulator (SERM), used in estrogen receptor-positive breast cancer treatment. Adverse effects include endometrial cancer risk and thrombotic complications.
• Aromatase inhibitors (anastrozole, letrozole): Inhibit estrogen production. Useful in postmenopausal women with ER-positive breast cancer.
• Antiandrogens (flutamide, cyproterone acetate): Block testosterone action. Used in prostate cancer. Hepatotoxicity can arise as a side effect with these drugs

Tyrosine Kinase Inhibitors

• Tyrosine kinases: Family of enzymes involved in cell signaling and growth.
• Inhibitors (imatinib): block tyrosine kinase activity, used in cancers involving affected pathways.
• Imatinib (Glivec): Used for CML (Philadelphia chromosome-positive) cancers.
• Adverse effects : fluid retention and hepatotoxicity.

Monoclonal Antibodies (-MABs)

• Monoclonal antibodies are used to target proteins on the surface of cancer cells or immune cells.
• They are administered intravenously (IV).

Miscellaneous Agents

• Bortezomib: Inhibits cellular proteasomal function, used in multiple myeloma.
• Biological response modifiers: Enhance the host's immune response to cancer cells. Interferons are examples.

Test your knowledge on cancer treatment, focusing on pharmacotherapy and monoclonal antibodies. This quiz covers mechanisms of action, side effects, and the classification of various cancer therapies. Challenge yourself with questions related to Imatinib, Bevacizumab, and combination chemotherapy.