Antineoplastic and Anticancer drugs Flashcards
Cancer definition
Loss in the normal control mechanisms that govern cell survival, proliferation, and differentiation
Oncogenes
Normally tightly regulate growth and differentiation of cells
Always on = cancer
Ex: Bcl-2 is up or downregulated in cancer
Tumor suppressor genes
Normally suppress overgrowth of cells
Missing = cancer
Ex: p53 is downregulated or absent in many cancers
4 most common cancers in Canada and their 4 year survival rate
Lung (17%)
Prostate (95%)
Breast (87%)
Colorectal (64%)
Stages of cancer
0: early cancer, not detectable
1-3: higher number reflects increase in size and spread
4: Invasion of other tissues and metastasis
3 ways cancer is treated
- Surgical removal of tumor
- Radiation (non-specific cytotoxicity and cell death)
- Chemotherapy
3 Processes chemotherapy targets
- Targets cell cycle (kill rapidly dividing cells - traditional agents)
- Target proliferation pathways (newer agents)
- Target cancer specific molecules (targeted anticancer agents)
3 Principles of chemotherapy
- Chosen dose must be tolerable (so that course can be completed - administer maximum tolerated dose (MTD))
- Dose and regimen must be chosen to maximize effectiveness (cyclic therapy - multiple growth cycles of tumor)
- Use combinations to increase efficacy
4 Classes of traditional antineoplastic agents
Alkylating and platinum agents (cross link DNA molecule)
Antimetabolites (nucleotide synthesis)
Topoisomerase inhibitors and antibiotics (interfere with DNA replication and transcription machinery)
Vinca alkaloids and taxanes (mitotic spindle)
Alkylating and Platinum Agents
Covalently (irreversibly) bind to DNA
Inhibits synthesis and function = death
Not cell cycle specific
Cyclophosphamide
Alkylating agent
Has a bis(chloroethyl)amine group
Needs to be activated in the liver (its a prodrug) - end up with Phosphoramide mustard
Metabolites cross link DNA (instead of H bonds holding the DNA together you get covalent bonds - cannot unwind)
Can bind to other molecules with similar functional groups - causes issues
Platinum containing agents
Similar to the alkylating agents, but do not necessarily contain alkyl groups
Cause inter and intra DNA strand cross links in cells, similar to mechanism of alkylating agents
Antimetabolites
Similar in structure to endogenous compounds (folic acid, nucleotide bases)
Prevents DNA synthesis
S phase specific
Purine antagonists
An antimetabolite
Ex: Mecaptopurine (structurally similar to adenine, interacts with enzymes involved in purine nucleotide synthesis)
Incorporated into RNA and DNA like adenine would be, but is unable to make correct base pair
Interferes with DNA replication and RNA translation
Pyrimidine antagonists
An antimetabolite
Ex: Flurouracil (Similar structure to uracil and thymine)
Binds thymidylate synthase, preventing further synthesis of thymidine nucleotides
Interferes with DNA replication and RNA translation
Folic acid antagonists
Folic acid is an essential co-factor in DNA and protein synthesis
Methotrexate is structurally similar to folic acid (an antimetabolite)
Topoisomerase 1 inhibitors
Ex: Topotecan
Bind to enzyme, produces a fixed complex that prevents further DNA replication and transcription
Halting the replication process signals cell death
Topoisomerase 2 inhibitors
Anthracyclin antibiotics (ex: doxorubicin) Prevents re-ligation of DNA strands by TopoII Strand breaks in DNA signal Cell death pathways
Anthracycline Antibiotics
Ex: Doxorubicin
Natural products from Strep.
Intercalate between strands, stabilize DNA-TopoII complex
Forms free radicals that can cause additional DNA damage
Side effect: cardiotoxicity