SBI242 Week 11: Cancer and Neoplastic Diseases

Study Notes

Neoplasia is the uncontrolled proliferation and spread of abnormal cells in the body
Characteristics of abnormal cells include:
- Uncoordinated growth that persists after the stimulus ends
- Inherited indefinitely by successive generations of cells
- Cancer hallmarks: sustaining proliferative signaling, evading growth suppressors, activating invasion and metastasis, enabling replicative immortality, inducing angiogenesis, resisting cell death, dysregulating cellular energetics, avoiding immune destruction, genome instability and mutation, and tumor-promoting inflammation

Antineoplastic drugs can be distinguished based on four broad strategies:
- Non-selectively blocking the cell cycle (cytotoxic drugs)
- Targeting hormone sensitive pathways (hormonal drugs)
- Targeting mutated pathway regulators (non-cytotoxic drugs)
- Enhancing the immune response to cancer (immunomodulatory drugs)

Act by interfering with cell proliferation or replication
Examples: alkylating agents, antimetabolites, corticosteroids, and somatostatin analogues
Common adverse effects:
- Myelosuppression (impaired bone marrow production of blood cells)
- Alopecia (hair loss)
- Gastrointestinal tract irritation
- Infertility
- Possible secondary malignancies
- Tissue damage after inadvertent extravasation (injection solution leaking into tissues)
- Febrile neutropenia (dose-related)

First class of modern era antineoplastic drugs
Mechanism of action: highly reactive alkyl groups bind to nitrogen atoms in guanine bases of DNA, causing breakage of the DNA strand and leading to apoptosis (programmed cell death)
Examples: nitrogen mustard analogues, nitrosoureas, and platinum-based agents

Impair the utilization of endogenous chemicals involved in metabolic processes
Mechanism of action: inhibit enzymes involved in pathways for nucleic acid synthesis and/or act as false 'building blocks', causing damaged polymers of nucleic acids to be built into impaired DNA and RNA in cancer cells
Examples: folic acid antagonists (e.g. methotrexate), and GnRH antagonist degarelix (blocks pituitary receptors, reducing testosterone levels and causing regression of prostate cancer)

Also referred to as 'targeted therapies'
Two main classes: small molecule kinase inhibitors (KIs) and antineoplastic monoclonal antibodies (mAbs)
Act by specifically blocking signal transduction pathways, causing impaired tumor growth and metastatic dissemination
Examples: PARP inhibitors, immune checkpoint inhibitors, and interferons

Act by inhibiting poly (ADP-ribose) polymerase (PARP) 1, an enzyme that repairs single-strand breaks or 'nicks' in DNA
Used in the treatment of breast or ovarian cancer due to mutations in BRCA1 or 2 proteins

Act by blocking immune checkpoints, such as CTLA4 and PD-1/PD-L1, to enhance T-cell-mediated destruction of cancer cells
Examples: CTLA4 inhibitors (e.g. ipilimumab), PD-1/PD-L1 inhibitors (e.g. nivolumab and pembrolizumab)

Naturally occurring small protein molecules with antiproliferative and immunostimulating actions
Used in the treatment of cancer, including malignant melanoma, mycosis fungoides, myeloproliferative disorders, and renal cell cancer
Examples: interferon alpha and interferon gamma

Levamisole: used in combination with 5-fluorouracil to treat colorectal carcinoma
Aldesleukin: a recombinant version of human interleukin-2 (IL-2), used to stimulate T-cell proliferation and enhance natural and lymphokine-activated killer cell activity

Stimulate neutrophil precursor cells to produce phagocytes, reducing duration of neutropenia and risk of infections
Used after myelosuppressant cytotoxic chemotherapy or bone marrow transplant to reduce immunosuppression adverse effects
Examples: filgrastim, lenograstim, and pegfilgrastim