Cancer Drugs
Long term survival means that even if the patient is not 100% cancer free, their organ systems and disease is kept under control, and the patient will live longer. The idea of a cure suggests that the patient has no more cancer cells.
Antibody Action
Fully human monoclonal antibodies are generated in transgenic mice that carry the human IgG locus. Monoclonal antibodies bind to a specific target on a tumor cell.
- Complement-Dependent Cytotoxicity (CDC): C1q binds to the antibody, activating the classical complement pathway, forming a MAC to lyse cancer cells.
- Complement-Dependent Cell-Mediated Cytotoxicity (CDCC): C3b from the complement cascade acts as an opsonin that facilitates phagocytosis and cytolysis via macrophages or NK cells.
- Antibody-Dependent Cell-Mediated Cytotoxicity / Phagocytosis (ADCC / ADCP): Macrophages and NK cells are recruited by bound IgG antibodies to induce lysis on tumor cells.
Mitotic Spindle Poisons
Arrest cells in the M phase of mitosis to inhibit the cell cycle.
Note: Peripheral nerves require functioning microtubules for transport of signaling molecules and substrates, so altering polymerization in any way will affect peripheral nerve function.
Vincristine
Inhibits the polymerization of microtubules
Paclitaxel
Inhibits the de-polymerization of microtubules
DNA Adduct Forming Drugs
Chemically modify a strand of DNA to inhibit replication.
Mechlorethamine
Cyclophosphamide
A prodrug activated in metabolism, resulting in alkylation at guanines, causing crosslinking and DNA damage and cell death. Can result in cystitis or bladder inflammation.
Cisplatin & Oxaliplatin
A prodrug activated in metabolism, resulting in alkylation of adenines, causing crosslinking and DNA damage and cell death. Can result in peripheral neuropathy and nephrotoxicity.
Extracellular Mechanisms
Cetuximab & Panitumumab
Inhibits EGFR-Epidermal Growth Factor Receptor (HER1), preventing uncontrolled proliferation.
Cancer cells utilize this EGFR by increasing the number of receptors or mutating the intracellular kinase domain for uncontrolled proliferation with or without the ligand.
Cetuximab therapy is used in solid tumors.
Drug resistance can occur from downstream activating mutations of KRas which is an EGFR
independent signal.
Adverse effects
Blocking this receptor results in cutaneous (rash) and GI (diarrhea) issues.
Trastuzumab & Pertuzumab
Inhibits Human Epidermal Growth Factor Receptor-2 (HER2), shutting down the cell cycle and promoting apoptosis.
HER2 is a an oncogene promoting proliferative and antiapoptotic signals for tumor development. Trastuzumab binds to domain IV and blocks downstream
signaling, activating ADCC to eliminate the tumor cell. Pertuzumab blocks domain II, preventing cross talk between HER2 and other HER receptors. Trastuzumab + Pertuzumab increases survival in conjunction.
Consequently, Trastuzumab can both stop metastasis and promote the immune system to eliminate residual tumor cells while Cetuximab can only do the former.
Adverse effects
Cardiac toxicity due to blockade of HER2 receptor and blockade of survival or repair signaling in cardiomyocytes. Even worse toxicity when paired with Doxorubicin. Pertuzumab is less toxic than Trastuzumab.
Thus, combination with Paclitaxel is recommended.
Bevacizumab
Inhibits Vascular Endothelial Growth Factor (VEGF) to normalize blood vessels, improve drug access to tumor cells, and improve immune cell recognition of tumors.
VEGF is a mediator of angiogenesis in cancer, providing the tumor with blood vessels for nutrients and oxygen.
An alternate use is Ranibizumab (altered Bevacizumab) is used to treat wet macular degeneration, improving vision.
Adverse effects
Use results in thrombotic events and bleeding disorders (thromboembolism) and GI perforations. Another major effect is hypertension.
Intracellular Drugs
Gefitinib, Erlotinib, Afatanib, & Osimertinib
Small Molecular Kinase inhibitors which reduces signal transduction. These are similar in effect to Cetuximab & Panitumumab.
They are used when EGFR is mutated, and the kinase inhibitor chosen depends on
the mutations in the EGFR.
Drug resistance can occur from downstream activating mutations of KRas which is an EGFR
independent signal.
Adverse effects
Blocking this receptor results in cutaneous (rash) and GI (diarrhea) issues. Osimertinib has less skin side effects because it mostly targets mutant EGFR and not wildtype EGFR.
Alectinib & Crizotinib
Inhibits the Anaplastic Lymphoma Kinase (ALK) pathway, which reduces metastasis risk.
In patients with non-small cell lung cancer, ALK translocates, producing an overactive signal transduction cascade. ALK pathway is independent of EGFR.
Imatinib
Inhibits the BCR-ABL pathway.
Patients with chronic myelogenous leukemia have a chromosomal translocation, resulting in constitutively active BCR-ABL pathway. This drug is also effective for gastrointestinal tumors.
Nucleotide Synthesis Inhibitors
5-Fluoro-Uracil (5-FU) & Capecitabine
Inhibits thymidylate synthetase.
Thymidylate synthetase converts deoxyuridine monophosphate (dUMP) into deoxythymidine
monophosphate (dTMP). 5-FU mimics dUMP but prevents the conversion from occurring.
Capecitabine is a prodrug that is given orally and is metabolized to 5-FU.
Methotrexate & Leucovorin
Inhibits dihydrofolate reductase.
Dihydrofolate reductase synthesizes tetrahydrofolate (THF), which is an important cofactor for
thymidylate synthetase which then disrupts thymidylate synthetase and the production of dTMP.
Leucovorin (folinic acid) mimics THF and can be used overcome the toxic effects of methotrexate overdose, called "leucovorin rescue". Leucovorin enhances the binding of 5-FU to Thymidylate Synthase and increases efficacy of 5-FU.
Combinations
FOLFIRI (Leucovorin): Folinic acid + 5-FU + Irinotecan. Treats colon cancer and pancreatic cancer.
Doxorubicin & Irinotecan
Inhibits Topoisomerase which causes DNA strand breaks during DNA replication and leads to cell death.
Doxorubicin can have cardiotoxicity from oxidative stress and iron chelation. This is
cumulative dose-dependent.
Combinations
FOLFIRI (Leucovorin): Folinic acid + 5-FU + Irinotecan. Treats colon cancer and pancreatic cancer.
AC: Adriamycin (Doxorubicin) + Cyclophosphamide. Treats breast cancer.