Workshop 7: Antineoplastic Drugs

Workshop 7: Antineoplastic Drugs

• Antineoplastic drugs are used to treat cancer
• Cancer is uncontrolled multiplication and spread of abnormal body cells

Neoplasm

• A neoplasm is a mass of tissue formed by abnormal, excessive, uncoordinated, purposeless proliferation of cells
• Abnormal cells are characterized by uncontrolled cell growth, loss of cell differentiation and function, invasiveness, and metastasis.

Pathophysiology of Cancer

• Genesis of Tumor Cells: Cancer occurs due to DNA mutations, mainly through two genetic changes:
  • Activation of proto-oncogenes: Proto-oncogenes control cell growth, division, and death. Mutations transform them into oncogenes, thus driving uncontrolled cell growth and malignant transformation.
  • Inactivation of Tumor Suppressor Genes: These genes normally prevent cells from becoming cancerous. Mutations lead to the disappearance of these checks and allows for abnormal growth.
• Four Key Characteristics of Cancer Cells:
  • Uncontrolled Proliferation: Cancer cells ignore normal cell cycle controls, leading to rapid and unchecked division
  • Dedifferentiation and Loss of Function: Cancer cells lose their specialized characteristics and ability to perform their normal functions, becoming less specialized
  • Invasiveness: Cancer cells invade surrounding tissues by breaking down the surrounding extracellular membrane
  • Metastasis: Cancer cells travel to distant sites throughout the body, establishing secondary tumors

Antineoplastic Therapy

• Drugs to Alter DNA: Cytotoxic drugs target DNA (e.g., alkylating agents, platinum compounds, antibiotics).
• Drugs Interfering with Growth or Survival of Tumor Cells: Targeted therapies are used to fight specific proteins or pathways that enable unregulated cell growth (e.g., hormone-dependent therapies, inhibitors of tyrosine kinases, and angiogenesis inhibitors).
• Drugs Activating the Immune System: Immunotherapy aims to energize the body's immune system in attacking cancer cells (e.g., immune checkpoint inhibitors, and cell therapies)

Cancer Types

• Carcinomas (80% of tumors): Originate from epithelial cells (e.g., lung, breast, colon, prostate)
• Sarcomas: Originate from connective or conjunctive tissues (e.g., muscles, bones, cartilages)
• Leukemias: Cancer of the bone marrow, impacting blood cells (e.g., erythrocytes, leukocytes, platelets).
• Lymphomas: Cancer of the lymphatic system (e.g., lymph nodes and lymphatic organs).

Common Unwanted Effects of Antineoplastic Drugs

• Immediate (few hours): nausea, vomiting, phlebitis, renal failure, anaphylaxis, anorexia, fever, hemorrhagic cystitis
• Precocious (days-weeks): leukopenia, myelosuppression, alopecia, stomatitis, ulcerations, diarrhea, psychosis
• Weeks-months: anemia, aspermia, hyperpigmentation, neuropathies, pulmonary fibrosis, cardiotoxicity
• Delayed (months-years): sterility, carcinogenesis, early menopause, osteoporosis

Strategies for Treatment

• Surgery, Radiotherapy, Chemotherapy and targeted therapies, and Immunotherapy are treatment strategies to target cancer.

Pharmacotherapy Treatment

• Primary therapy: treatment used alone.
• Neoadjuvant therapy: treatment given before surgery.
• Adjuvant therapy: treatment given after surgery.
• Combination therapy: using multiple drugs to improve efficacy and reduce resistance, including several drugs with different mechanisms or actions.
• Minimizing toxicity in normal tissue: using treatment in cycles or metronomic posology to provide the treatment effects while minimizing the adverse effects on normal cells.

Chemotherapy Resistances

• Mechanisms leading to resistance:
  • Alteration in membrane transport system (MDR1)
  • Increased enzymatic deactivation
  • Utilization of alternative pathways
  • Apoptosis resistance (mutation p53)
  • Reparation of DNA damage (ERCC11)
  • Decreased drug accumulation
  • Altered drug metabolism and detoxification
  • Mutations in drug targets
  • Target molecule alteration
• Tumor cells reducing cytotoxic drug accumulation by overexpression of P-glycoprotein.
• Resistance causes by inefficient activation of the drug, rapid repair of lesions, or alteration of the target.
• Modification of the p53 gene and excessive expression of the Bcl-2 gene family contribute to drug resistance.

Therapeutic Strategies

• Alter DNA tumor cells
  • Damage DNA
  • Affect DNA synthesis and stability
• Alter signals involved in growth and differentiation of tumor cells
  • Hormones
  • Tumor Pathways
• Immune system activation
  • Immune Response
  • Checkpoint Inhibitors
  • Cell Therapies
  • Vaccines

Cytotoxic drugs in the cell cycle

• Cytotoxic drugs act on different phases of the cell cycle.
• Drugs which target DNA synthesis, and integrity.
• Drugs which target DNA damaging agents, for example alkylating agents. Drugs which target DNA repair.

Alkylating Agents

• Nitrogen Mustard: Cyclophosphamide

• Nitrosureas: Carmustine, Lomustine

• Others: Dacarbazine, Temozolamide

• Mechanism of Action: They damage cancer cell DNA via cross-linking between DNA strands, hindering DNA replication and transcription.

• Adverse effects: mutagenesis, carcinogenesis, alopecia, depression of bone marrow function and sterility.

Nitrogen Mustards

• Cyclophosphamide: Oral administration, preferred oral route, crosses blood-brain barrier. Active metabolites alkylate DNA via hepatic cytochrome P450 enzyme. Broad spectrum (non-Hodgkin lymphoma, breast, lung cancer). Specific toxicities include hemorrhagic cystitis, neurotoxicity, and hepatic toxicity.
• Metabolism of Cyclophosphamide: Phosphoramide mustard to aldophosphamide to acrolein, leading to hemorrhagic cystitis. Mesna is used to mitigate this effect by creating a sulfur-containing compound which reacts with acrolein.

Nitrosureas

• Carmustine and Lomustine: Cross blood-brain barrier (liposolubility), metabolites appear in the urine, used in brain tumours

Others

• Temozolomide, Dacarbazine: Cross blood-brain barrier, used for specific tumors including malignant melanoma

Platinum Compounds

• Intercalating agents: Cisplatin, Carboplatin
• Mechanism of Action: Intrastrand cross-links between neighboring guanine residues, preventing DNA replication.

Antibiotics-Antraciclines

• Doxorubicin, Daunorubicin
• Mechanism of Action: DNA intercalation, inhibiting DNA and RNA synthesis, generation of free radicals.
• Specific Toxicities: Cardiotoxicity, hyperpigmentation
• Clinical Uses: Breast, bladder, ovarian cancer, sarcomas, carcinomas, Hodgkin lymphoma

Other Intercalating Agents

• Trabectedin: IV administration, monotherapy. Advanced sarcoma and combined therapy with doxorubicin or platinum.
• Mechanism of action: DNA intercalation in tumor cells interrupts the cell cycle, macrophages are involved in the response.

More Effective Drugs in Cells with High Proliferation Rate

• Adverse effects: bone marrow depression (myelotoxicity), fatigue (anemia), developmental delay (growth in children), infertility, teratogenicity, poor wound healing, alopecia, mutagenicity, carcinogenicity, gastrointestinal problems.

Antimetabolites

• Structural analogs of metabolites essential for cell growth and division (e.g., folate, purine, and pyrimidine analogs)
  • Folate antagonists: Methotrexate
  • Pyrimidine antagonists: 5-fluorouracil, cytarabine, gemcitabine
  • Purine antagonists: 6-mercaptopurine, 6-thioguanine, azathioprine
• Mechanisms of action: Inhibition of specific enzymes involved in nucleotide synthesis, preventing DNA replication and cell division.

Topoisomerase Inhibitors

• Topoisomerase I: Camptothecin analogs (irinotecan, topotecan)
• Topoisomerase II: Podophyllotoxins (etoposide, teniposide), anthracyclines (doxorubicin, daunorubicin)
  • Mechanism: Inhibiting topoisomerases, preventing DNA replication, cell division, promoting strand breaks leading to DNA damage
  • Clinical uses: Different types of cancers.
  • Adverse Effects: Myelosuppression

Microtubule Inhibitors

• Vinca alkaloids (vincristine, vinblastine, vinorelbine)
  • Mechanism: Disrupt microtubule function, blocking cell division
  • Clinical uses: Lymphatic and solid tumors
  • Adverse effects: Myelosuppression, peripheral neuropathy
• Taxanes (taxol, paclitaxel, docetaxel)
  • Mechanism: Stabilize microtubules, blocking cell division
  • Clinical uses: Advanced ovarian and breast cancer
  • Adverse effects: Neutropenia, neurotoxicity, bradycardia, fluid retention, and hypersensitivity

PARP Inhibitors

• Olaparib
• Mechanism of action: Inhibits the PARP enzyme, preventing DNA repair in cancer cells with defective DNA repair mechanisms (e.g., BRCA mutations), leading to tumor cell death.
  • Clinical uses: Cancers associated with damaged DNA repair pathways.

Hormone-Dependent Therapies

• Breast cancer (estrogen receptor-positive): Tamoxifen (SERM), fulvestrant (pure antagonist), anastrozole (Aromatase inhibitor)
• Breast and Prostate cancer: Leuprolide (GnRH analogue).
• Prostate cancer: Finasteride, Dutasteride (5-alpha-reductase inhibitors), bicalutamide (Antagonist of androgens receptors).
• Mechanisms of action: Interrupt hormone signaling pathways in hormone-dependent tumors, hindering tumor growth and reducing hormone dependence

Specific Tumor Pathways

• Inhibitors of tyrosine kinases, RAF kinases, and cyclin-dependent kinases
• Monoclonal antibodies (MAB) targeting specific tumor-associated proteins (e.g., rituximab, trastuzumab, ibrutinib)

Angiogenesis Inhibitors

• Bevacizumab, Vandetanib, Sunitinib, Sorafenib, Talidomide, Lenalidomide
• Mechanism of action: Inhibiting the growth of new blood vessels, hindering tumor growth and metastasis.

Immune System Activation

• Immune checkpoint inhibitors (e.g., ipilimumab, nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab)
• Cell therapy (e.g., T-cell therapies, CAR T-cell therapies)
• Vaccines
• Mechanisms of action: Reinforces the body's immune system to recognize and destroy cancer cells, potentially causing tumors to regress, or preventing them from growing or metastasizing.

Treatment Examples

• Non-Hodgkin Lymphomas: CHOP regimen (cyclophosphamide, doxorubicin, vincristine, prednisone) + Rituximab
• Testis Cancer: BEP (bleomycin, etoposide, cisplatin) or PEI (cisplatin, etoposide, ifosfamide) regimens

Clinical Uses of Newer Anticancer Drugs

• Trastuzumab: breast cancer (HER2)
• Bevacizumab: metastatic colon cancer (VEGF)
• Rituximab: non-Hodgkin lymphoma (CD-20)
• Panitumumab: metastatic colon cancer (EGFR)
• Alemtuzumab: chronic lymphocytic leukemia (CD-52)
• Nivolumab: metastatic melanoma and non-small cell lung cancer (PD1)
• Atezolizumab: non-small cell lung cancer, renal cancer, and bladder cancer (PDL1)

This quiz covers essential concepts of antineoplastic drugs used in the treatment of cancer. It delves into the pathophysiology of cancer, including the role of DNA mutations in tumor genesis and the characteristics of cancer cells. Enhance your understanding of neoplasms and the crucial aspects of cancer treatment.