Microtubule inhibitors (M phase)

• Chris Christie closed lanes at George Washington Bridge
  • He is toxic
• Need to take taxi
• People boo

Cell‑cycle independent agents

• Alkylating agents
  • Busulfan
  • Nitrogen mustards
    • Cyclophosphamide
    • Ifosfamide
  • Nitrosoureas
    • Carmustine
    • Lomustine
  • Procarbazine
• Platinum compounds
  • Cisplatin
  • Carboplatin
  • Oxaliplatin
• Dactinomycin (an antibiotic)

"G1 inhibitors" is incorrect

• Cyclophosphamide
  • Belongs to Nitrogen mustards / Oxazaphosphorines
  • Indications
    • Malignancies
      • Solid tumors (e.g., breast cancer, ovarian cancer, small cell lung cancer)
      • Leukemias
      • Lymphomas
      • Multiple myeloma
    • Nonneoplastic conditions
      • Autoimmune diseases (e.g., systemic lupus erythematosus, granulomatosis with polyangiitis)
      • Nephrotic syndrome
  • Adverse effects
    • The extensive DNA damage inhibits replication and causes apoptosis of malignant cells. However, nonmalignant cells are also affected and can aquire new mutations (due to erroneous DNA repair) that contribute to development of secondary malignancies. For instance, DNA alterations in hematopoietic stem cells can lead to the formation of treatment-related myeloid neoplasms.
    • Bladder toxicity: metabolism of oxazaphosphorines produces the urotoxic substance acrolein
      • Hemorrhagic cystitis: inflammation of the bladder, damaging to the epithelium and blood vessels
      • Bladder carcinoma
    • Myelosuppression
    • Syndrome of inappropriate antidiuretic hormone secretion (SIADH)
    • Pulmonary toxicity
    • Cardiac toxicity
    • Infertility
    • Fanconi syndrome (ifosfamide)
    • Neurotoxicity (ifosfamide)

Detoxifying agents for antineoplastic treatment

• Platinum-based agents
  • Prevent Nephrotoxicity
  • Amifostine: free radical scavenger
  • IV saline: induces chloride diuresis → ↑ urine chloride concentration → ↓ cisplatin reactivity
• Oxazaphosphorines
  • Prevent Bladder toxicity
    • Hemorrhagic cystitis
    • Bladder carcinoma
  • Mesna (2-MErcaptoethane Sulfonate Na) and fluids
• Antifolates
  • Prevent
    • Myelosuppression
    • Mucositis
    • Hepatotoxicity
    • Pulmonary fibrosis
  • Leucovorin (folinic acid)
    • Precursor of tetrahydrofolate
    • Application 24 h after the administration of antifolates
• Anthracyclines
  • Prevent Cardiotoxicity
  • Dexrazoxane: iron chelating agent

Antimetabolites (S phase)

• See De novo pyrimidine and purine synthesis
• Purine antagonists
  • Azathioprine is the prodrug of 6-MP
    • Azathioprine and 6-MP are purine analogs, so they are metabolized to inactivate forms by xanthine oxidase like purines
    • When taken together, allopurinol inhibits the metabolism of azathioprine, leading to increased levels of 6-mercaptopurine. This can result in potentially severe side effects such as bone marrow suppression, leading to leukopenia, thrombocytopenia, or anemia. Therefore, when used together, azathioprine dose typically needs to be reduced by 50-75%.
    • See Gout#Treatment, Lesch-Nyhan syndrome
• Antifolates
  • Methotrexate
    • Adverse effects
      • Myelosuppression, anemia
      • Hepatotoxicity, hepatic fibrosis
      • Pulmonary fibrosis, pneumonitis
      • Nephrotoxicity
      • Mucositis (e.g., oral ulcerations)
      • Birth defects (due to folate deficiency), e.g., neural tube defects

Topoisomerase inhibitors (G2 phase)

• Topoisomerase I
  • Cleaves only one of both DNA strands
  • Has nuclease activity to cut DNA strands
  • And has ligase activity to reseal the ligated strand
  • Does not require ATP
• Topoisomerase II
  • Cleaves both DNA strands for larger structural alterations of DNA
  • Requires ATP

Antitumor antibiotics

Protein kinase inhibitors

CDK inhibitors

• Palbociclib
• Inhibition of cyclin-dependent kinase 4 and 6 → inhibition of cancer cell growth and induction of apoptosis
• Indications
  • Metastatic breast cancer
  • Myelosuppression
• Side effects
  • Pulmonary toxicity (e.g., pneumonitis)

Anticancer treatment-related complications

Chemotherapy-induced nausea and vomiting (CINV)

• Acute-phase CINV (<24 hours after chemotherapy) is mediated primarily by the release of serotonin from intestinal enterochromaffin cells that have been damaged by chemotherapy. Serotonin stimulates vagal afferent fibers (5-HT3 receptors) in the bowel wall, which project to the brainstem and stimulate the vomiting reflex. Therefore, serotonin receptor antagonists (eg, ondansetron) can be used for treatment.
• Delayed-phase CINV (1-5 days after chemotherapy) is mediated primarily by increased levels of substance P in the brainstem due to chemotherapy-associated emetic stimuli in the cerebrospinal fluid and bloodstream. Substance P binds to and activates the neurokinin-1 (NK1) receptor in areas of the brainstem that mediate vomiting (eg, nucleus tractus solitarius, area postrema). Therefore, NK1 receptor antagonists (eg, aprepitant, fosaprepitant) are often used for treatment.