Anineoplastic and Anticancer Agents - Farrell Flashcards
What is cancer?
Loss in normal mechanisms that govern cell survival, proliferation, and differentiation
They keep growing, even where there is no space, when most cells stop
Causes of cancer (2)
- Oncogenes
2. Tumor suppressor genes
Oncogenes
Normally tightly regulated growth and differentiation of cells
ie. Bcl-2: unregulated or deregulated in cancer
Tumor suppressor genes
Normally suppress overgrowth of cells
ie. p53: down regulated or absent in many cancers
Causes of cancer
Genetics
Environmental
Most common forms of cancer
Lung, prostate, breast, colorectal
Cancer pathophysiology (3)
- Initiation
- Promotion
- Progression
Initiation
Chemical or physical carcinogen causes mutation
Not identified as foreign by immune system
Promotion
Growth factors and promoters of cell proliferation
Progression
Transformation to malignant from benign
Further mutation and variation with tumor
Stages of cancer
Stage 0-IV
0: early, not detectable
I-III: higher number reflects size and spread
IV: invasion of other tissues and metastasis
How is cancer treated? (3)
- Surgical removal of tutor
- Radiation
- Chemotherapy
Targets of chemotherapy (3)
- Target cell cycle
- Target proliferation pathways
- Target cancer specific molecules
Traditional antineoplastic agents
Target cell cycle Kill rapidly dividing cells 1. Alkylating and platinum agents 2. Antimetabolites 3. Topoisomerase inhibitors and antibiotics 4. Vinca alkaloids 5. Taxanes
Newer anticancer drugs
Target proliferation pathways
Target anticancer agents
Target cancer specific molecules
- Cellular markers
- Growth and proliferation
- Angiogenesis
- Hormone sensitive growth
Principles of chemotherapy (3)
- Chosen agent must be tolerable
- Dose and regiment must be chosen to maximize effectiveness
- Use combinations to increase efficacy
MTD
Maximum tolerated dose
Cyclic therapy
Multiple cycles of therapy to combat multiple growth cycles of tumor
Alkylating agents
Crosslink DNA causing damage and death
Groups of agents based on their structures
1. Bis(chloroethyl)amine group
2. Platinum containing agents
Bis(chloroethyl)amine
Alkylating agent
ie. Cyclophosphamide
Cyclophosphamide
Needs to be activated in liver
Metabolites cross-link DNA by binding
Can bind other molecules with similar functional groups (SH, OH, NH) like lipids and proteins
Platinum containing agents
Similar to alkylating agents but do not necessarily contain alkyl groups
Cause inter and intra DNA strand cross-links in cells
Antimetabolites
Similar in structure to endogenous compounds like Folic acid and nucleotide bases
Interfere with nucleotide synthesis
Prevent DNA synthesis
ie. Mercaptopurine, fluorocuracil, folic acid antagonists
Mercaptopurine
Structurally similar to adenine
Interacts with enzymes involved in purine nucleotide synthesis
Incorporated into RNA and DNA but unable to correctly basepair
Interferes with DNA replication and RNA translation
Fluorouracil
5-FU
Similar in structure to uracil and thymine
Binds to thymidylate synthase
Prevents further synthesis of thymide nucleotides
Folic acid antagonists
Folate, folic acid, vit B9
Essential cofactor in DNA and protein synthesis
Includes methotrexate
Methotrexate
Structurally similar to folic acid
Prevents nucleotide synthesis by eliminating cofactor
Topoimerase I inhibitors
ie. Topotecan
Bind to topoimerase I
Produces complex that prevents further DNA replication and transcription
Halting replication process signals cell death
Topotecan
Topoimerase I inhibitor, fixed enzyme to DNA
Replication cannot procede
Topoimerase II inhibitors
Includes Anthracycline antibiotics
Prevents relegation of DNA by TopoII
Strand breaks in DNA signals cell death pathways
Anthracycline antibiotics
ie. Doxorubicin
Natural products isolated from Strep species
Intercalate between strands and stabilize DNA-TopoII complex
Forms free radicals that can cause DNA damage
Cause cause cardiotoxicity