Pharm II (Chemo 1a)
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What are the Goals of Chemotheorpy?
- 1. to cure malignancies
- 2. to Improve cure rates
- 3. to spare organ functions
- 4. to paliate symptoms
What do Alkylating agents do?
They have vesican properties (cause vessicles)
What is a Alkylating agent?
Alkane-- C-H or C-C SINGLE BONDS
Alkyl group-- an Alkane with a missing hydrogen. Very reactive, forms adducts with nucleophylic molecules.
What is an Anti-Matabolite?
A substance bearing a close structural resemblance to substance required for normal physiologic functioning. Usually implies the inhibition of synthesis or DNA,RNA or Protein.
What are the naturally occurring agents?
They are found in nature with very minimal modification for use. Usually from fungi (antibiotics) or plants( plant alkaloids)
What is Dauorubicin?
It is a naturally occurring agent that is from Streptomyces (red dye). 2nd most important member of the NC agents.
Name some Alkalizing agents
- 1.Nitrogen mustard
What are some Nitrogen Mustard derivatives?
- - chlorambucil
- - melphalan
- - cyclophosphamide
- - ifosfamide
What are some Nitrosoureas?
- - BCNU
- - CCNU
- - mCCNU
- - streptozocin
What are some other Alkylators?
- - thiotepa
- - procarbazine
- - dacarbazine
name some Antimetabolites
- - methotrexate
- - pemetrexed
- - 5-FU
- - ARA-C
- - gemcitabine
- - 6-TG
- - 6-MP
- - hydroxyurea
What are some naturally occuring compounds?
- fungal derived (antibiotic)
- - anthracyclines
- - mitoxantrone
- - actinomycin-D
- - bleomycin
- plant derived
- - vinca alkaloids
- - podophyllotoxins
- - camptothecins
- - taxanes
What are some Miscellaneous Agents?
- - platinum derived
- - l-asparaginase
What do Anti-Neoplastics do?
- 1. Inhibit DNA synthesis
- 2. Inhibit spindle function
- 3. Undermine growth regulation
- 4. Starves target of nutrients and oxygen
- 5. Acquire resistance
What is the princile of log kill?
A mass has to be 1 gram or 1,000,000,000 cells to be detectable
1kg is lethal
chemo kills a constant fraction of the cancer cells. Absolute kill does NOT occur.
When is Chemo most effective?
During Cycling (dividing)
What controls the cell cycles?
Tyrosine kinases, which are activated by regulating proteins called cyclins and inhibited by proteins such as p16. Mutation or loss of p16 can result in relentless proliferation of cancer cells
What is Gompertzian growth?
The idea that as the Tumor gets larger, the rate of growth decreases due to hypoxia.
What are Specific for the different phases of the cell cycle?
- S phase - DNA synthesis
- M phase - mitotic spindle synthesis
- Vinca alkaloids
What are the Cell cycle NON-Specific agents?
- G0 - resting phase
- Platinum compounds
What are some common Properties of Alkylators?
1. act through covalent bonding of alkyl groups
2. generate highly reactive positively charged intermediates
3. combine with electron-rich “nucleophilic” groups (amino, phosphate, sulfhydryl, or hydroxyl moities)
4. may contain one or two functional groups
5. Alkylation of DNA bases appears to be major cause of lethal toxicity
6. Monofunctional – single strand breaks
7. Bifunctional – cross linking
8. Toxicity worse in cells deficient in DNA repair enzymes
Where do the Alkylators usually attack the Nucleophilic groups?
at the N-7 position of Guanine
What are some Methodes tumor cells develope resistance to Alkylators?
1.Decreased transport across cell membranes (gene amp)
2.Increased intracellular thiol concentration (gene amp)
3.Increased enzymatic detoxification of reactive intermediates (gene amp)
4.Alteration in DNA repair enzymes (gene mutation)
What are some Specific Properties of the Nitrosoureas (Alkylators)?
What acts as the Electron leaving group?
- -Fat Soluble
- -Prolonged bone Marrow Suppression
What does Dacarbazine still play a role in?
What is Nitrogen Mustard used for?
Part of MOPP protocol for Hodgkins
What is Chorambucil used for?
- Low grade lymphomas (CLL)
- Absorbed orally
What is Melphalan used for?
- Multiple Myeloma
- High dose BMTransplant
When is the activity of Cyclophosphamide?
- - well absorbed orally
- - widest clinical usage
- - active intermediate
- (phosphoramide mustard)
- - main toxicity is myelosuppression
- - useful in breast cancers, lymphomas, leukemias
When is Ifosfamide used?
Testicular cancer, Sarcomas, Lung cancer
note: the reactive intermediate (acrolein) can be modified with MESNA
What is MESNA?
It supplies the Thiol group that binds to the reactive intermediate of Ifosfamide (acrolein) and inactivates it.
What is Nitrosoureas activity?
It is fat soluble so it crosses the BBB and is thus a good treatment in Melanoma and Brain tumors.
plays a role in Islet cell tumors.
- -DTIC- used in melanoma and ABVD protocol for hodgkins
- - Procarbazine- used in hodgkins and brain tumors
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