Anticancer agents II

• Considerations before administering chemotherapy and limitations of classical chemotherapy therapies:

  • Very advanced disease
  • Existing bone marrow depression
  • Presence of active infection
  • Limitations include:
  • Most target cell proliferation but not invasion and metastasis
  • Lack of selectivity leading to toxic effects on marrow
  • Lack of sensitivity
  • Total elimination of the tumor may not be possible
  • Development of resistance
• Role of hormone therapy in cancer treatment:

  • Hormone therapy is crucial for hormone-sensitive cancers like breast, endometrial, and testicular cancers
  • Selective estrogen receptor modulators and aromatase inhibitors are key in hormone therapy
• Targeted strategies for cancer therapy:

  • Examples include trastuzumab, imatinib, and angiogenesis inhibition strategies
  • Targeted therapies are more specific and less toxic compared to classical cytotoxic agents
• Hormones as anti-cancer targets:

  • Tumors from hormone-sensitive tissues can be hormone-dependent
  • Hormone therapy is better tolerated in patients with hormone-sensitive advanced breast cancer compared to cytotoxic chemotherapy
• Hormone antagonists:

  • Bind the receptor and block its normal action
  • Examples include Tamoxifen (anti-estrogen) and Flutamide (anti-androgen)
• Tamoxifen:

  • Competes with natural estrogens for binding to estrogen receptor
  • Acts as a selective estrogen receptor modulator (SERM)
  • Effective in early and advanced estrogen receptor-positive breast cancer
• Aromatase inhibitors:

  • Inhibit the enzyme aromatase responsible for estrogen synthesis
  • Used in estrogen receptor-positive breast and ovarian cancer, especially in postmenopausal women
• Precursor relationships of steroid hormones:

  • Involves enzymes like aromatase responsible for key steps in estrogen biosynthesis
• Oestrogen binds to the estrogen receptor leading to activation of transcription in different tissues

  • Tamoxifen binds to the estrogen receptor differently, inhibiting the growth of breast cancer without causing osteoporosis
• Aromatase inhibitors like anastrozole and letrozole compete reversibly for the androstenedione binding site on the aromatase enzyme
• Aromatase inhibitors like exemestane irreversibly inhibit the aromatase enzyme, while non-steroidal inhibitors compete reversibly for the androstenedione binding site
• Tamoxifen competes with natural estrogens for binding to the estrogen receptor and is effective in early and advanced estrogen receptor-positive breast cancer
• Targeted strategies for cancer therapy involve specific examples like trastuzumab, imatinib, and angiogenesis inhibition strategies
• New therapies in cancer biology:

  • Targeted agents are less toxic and more specific to each cancer type
  • Aimed at specific cellular pathways and molecular targets
• Inhibition of peripheral aromatization:

  • Aromatase inhibitors like exemestane and anastrozole inhibit the conversion of androgens to estrogens
• Considerations before administering chemotherapy include very advanced disease, existing bone marrow depression, and the presence of active infection

  • Limitations of classical chemotherapy include lack of selectivity, sensitivity, and the potential for resistance
• Types of anticancer therapy:

  • Classical anticancer (cytotoxic) agents
  • Hormone therapy
  • Targeted therapy
• Hormone therapy is better tolerated in patients with hormone-sensitive advanced breast cancer compared to cytotoxic chemotherapy
• Classical anticancer agents include:

  • Antimetabolites
  • Alkylating agents
  • Cytotoxic antibiotics
  • Plant alkaloids/microtubule inhibitors
• Hormone therapy includes antagonists, agents that inhibit hormone synthesis, and hormones with opposing actions to inhibit tumor growth
• Hormones as anti-cancer targets are crucial in hormone-sensitive cancers like breast, endometrial, and testicular cancers
• Aromatase inhibitors inhibit the enzyme aromatase responsible for estrogen synthesis and are frequently used in estrogen receptor-positive breast and ovarian cancer
• New therapies in cancer biology are more specific and less toxic, targeting specific cellular pathways and molecular targets
• Classical anticancer agents include antimetabolites, alkylating agents, cytotoxic antibiotics, and plant alkaloids/microtubule inhibitors
• Types of anticancer therapy include classical anticancer agents, hormone therapy, and targeted therapy
• Oestrogen binds to the estrogen receptor, leading to activation of transcription in different tissues

  • Tamoxifen binds differently, inhibiting breast cancer growth without causing osteoporosis
• Aromatase inhibitors like anastrozole and letrozole compete for the androstenedione binding site on the aromatase enzyme
• Emerging therapies aimed at new molecular targets include targeting specific cellular pathways such as receptor overexpression, over/underactive cell control pathways, and new blood vessel growth
• HER2 (ERBB2) gene produces the HER2 protein, which plays a role in controlled cell growth and regulated rate of division
• Excess HER2 protein leads to uncontrolled growth and an increased rate of division
• HER2 over-expression by tumour cells is found in approximately 15% of women with breast cancer
• FISH (fluorescent in situ hybridization) is used to detect HER2 gene amplification
• Trastuzumab (Herceptin) is a monoclonal antibody against HER2 that blocks HER2/receptor dimerization and inhibits proliferation of cancer cells overexpressing HER2
• Trastuzumab (Herceptin) also acts by ADCC (antibody-dependent cell-mediated cytotoxicity) and is associated with cardiac dysfunction in 2-7% of cases
• Herceptin is used for breast, oesophageal, and gastric cancer
• Tyrosine kinases are enzymes that regulate pathways controlling proliferation, survival, and angiogenesis
• Tyrosine kinases include receptor tyrosine kinases (e.g., VEGFR, EGFR, HER2, PDGFR) and non-receptor tyrosine kinases (e.g., Abl, Rb)
• A translocation between chromosomes 9 and 22 produces the BCR-ABL oncogene and fusion protein, constitutively active in 95% of CML patients
• Selective tyrosine kinase inhibitors like Imatinib target Bcr/Abl, PDGFR, and c-kit proteins and are used to treat Ph+ chronic myeloid leukaemia (CML) and gastrointestinal stromal tumours (GISTs)
• Imatinib blocks ATP binding to BCR-ABL, inhibiting its kinase activity and subsequent cellular events