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)