31 History of Cancer Drugs Flashcards
2 general classes of cancer drugs developed
ChemoTx
Single-molecule targeted Tx
Limitation of chemoTx?
Targets rapidly-proliferating cells
= lacks SPECIFICITY (side effects)
Name the 2 early scientists who had early approaches to cancer Tx
What did they discover?
Coley - gram +/- bac for lymphoma + sarcoma (immuneTx)
Beatson - Oophorectomy for breast cancer patients (lead to Tamoxifen for ER+ tumors)
Name the 5 classes of cytotoxic drugs (acronym)
AAPTM Antimetabolites Alkylating drugs Platinating drugs Topoisomerase poisons - CPT, Etopiside, Doxorubicin Mitotic poisons
How were Alkylating drugs discovered
Accidental release of MUSTARD GAS caused immunosuppression
Examples of alkylating drugs
Cyclophosphamide (interstrand x-links) Nitrogen mustard (interstrand x-links) TMZ + Dacarbazine (methylating)
Concept of antimetabolities?
MIMIC metabolites = block ENZYMES
2 types of antimetabolites?
What do they block?
Folic acid (MTX) - blocks DHFR (depletes dTMP = block DNA synthesis) Nucleic acid ANALOGS - incorporate into DNA directly to cause stress signal
Give examples of nucleic acid analogs (antimetabolites0
5-FU
6-mercaptopurine
Ara-C (Cytosine analogs)
Examples of ANTIBIOTICS that interact directly with DNA?
Topoisomerase poisons
- Doxorubicin
- Daunorubicin
- Actinomycin D
- Mitomycin D
How do MITOTIC poisons work?
Examples?
Bind b-subunit of tubulin to disrupt MTs
eg. Alkaloids (Vinblastine, Vincristine)
Name 3 plant products and the plant they come from
Paclitaxel - Yew tree
Etopisides - Mandrake root toxic
Camptothecin - Camptotheca tree
Name a SYNTHETIC compound and its MoA
Cisplatin = forms INTRAstrand x-links to block CC
What was a major LIMITATION for early drug screening?
Lack of effective screening MODELS
Name the 3 classes of MODELS developed
Tumor models
Cell cultures
NCI testing program
Advantages of transplantable TUMOR models
- Standardisation of models
* Screening MANY compounds at once
Example of a tumor transplant model?
Nude mice - immunodeficient
Limitations of mice models
Unethical
Species differences (lack some targets)
Expensive
Advantages of CELL CULTURES
HUMAN cell lines = species-specific
96-well technology = HIGH throughput analysis
Commercially available cell lines
How does NCI testing work?
Candidate drugs screened against a PANEL of 60 cell lines
= FINGERPRINT of IC50 values obtained
= look for drugs with UNIQUE fingerprints (new Tx?)
Advantages of NCI testing?
- Standardisation
- High-throughput analysis
- NEW Tx
ADVANTAGES of molecularly-targeted Tx
SPECIFICITY improved (exploits genetic abnormalies and signalling pathways of tumor cells)
What technique is particularly useful for KINASES?
Why?
Molecular modelling (kinases have a BINDING-POCKET)
Give 4 examples of molecularly-targeted Tx
HIRG Herceptin Rressa Rituximab Gleevac
What is Rituximab?
What cancer does it target?
Chimeric monoclonal antibody, targets B-cell antigen CD20 (kills MATURE cells only, naive B-cells don’t exp CD20)
= non-Hodgkin’s Lymphoma
What is Herceptin?
What cancer does it target?
Humanised recombinant monoclonal antibody
Targets HER2 (part of EGFR heterodimer)
= present in ~30% breast cancers
What is Iressa?
What cancer does it target?
Inhibits RTK activity of EGFRs
= breast, ovarian, lung cancers
What is Gleevac?
What cancer does it target?
100% selective for Bcr-Abl fusion protein
= CML, GI stromal tumors
2 classes of VASCULAR targetting drugs
Differences between them?
Anti-ANGIOGENIC - blocks growth of NEW BVs
Anti-VASCULAR - acts on MATURE BVs
Downstream effects of anti-VASCULAR agents on the tumor?
Disrupt BF = induce hypoxia + necrosis of tumor
Give an example drug for:
Anti-angiogenic
Anti-vascular
Avastin (anti-angiogenic)
DMXAA (anti-vascular)
What is Avastin?
What cancer does it target?
Humanised monoclonal antibody, inhibits VEGF (anti-angiogenic drug)
= CRC (in combo with 5-FU)
What is DMXAA
Anti-vascular drug
= EC dmg/apoptosis
= vasoPERM
= disrupt tumor BF
= tumor HYPOXIA + NECROSIS
