Pharm II (Chemo 1a)

• 1. to cure malignancies
• 2. to Improve cure rates
• 3. to spare organ functions
• 4. to paliate symptoms

They have vesican properties (cause vessicles)

Alkane-- C-H or C-C SINGLE BONDS

Alkyl group-- an Alkane with a missing hydrogen. Very reactive, forms adducts with nucleophylic molecules.

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.

They are found in nature with very minimal modification for use. Usually from fungi (antibiotics) or plants( plant alkaloids)

It is a naturally occurring agent that is from Streptomyces (red dye). 2nd most important member of the NC agents.

• 1.Nitrogen mustard
• 2.Nitrosoureas
• 3.Others

• - chlorambucil
• - melphalan
• - cyclophosphamide
• - ifosfamide

• - BCNU
• - CCNU
• - mCCNU
• - streptozocin

• -busulfan
• - thiotepa
• - procarbazine
• - dacarbazine

• - methotrexate
• - pemetrexed
• - 5-FU
• - ARA-C
• - gemcitabine
• - 6-TG
• - 6-MP
• - hydroxyurea

• fungal derived (antibiotic)
• - anthracyclines
• - mitoxantrone
• - actinomycin-D
• - bleomycin
• plant derived
• - vinca alkaloids
• - podophyllotoxins
• - camptothecins
• - taxanes

• - platinum derived
• - l-asparaginase

• 1. Inhibit DNA synthesis
• 2. Inhibit spindle function
• 3. Undermine growth regulation
• 4. Starves target of nutrients and oxygen
• 5. Acquire resistance

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.

During Cycling (dividing)

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

The idea that as the Tumor gets larger, the rate of growth decreases due to hypoxia.

• S phase - DNA synthesis
• Antimetabolites
• M phase - mitotic spindle synthesis
• Vinca alkaloids
• Taxanes

• G0 - resting phase
• Alkylators
• Antibiotics
• Platinum compounds

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

at the N-7 position of Guanine

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)

• -Fat Soluble
• -Prolonged bone Marrow Suppression

CL

Melanoma

Part of MOPP protocol for Hodgkins

• Low grade lymphomas (CLL)
• Absorbed orally

• Multiple Myeloma
• High dose BMTransplant

• - well absorbed orally
• - widest clinical usage
• - active intermediate
• (phosphoramide mustard)
• - main toxicity is myelosuppression
• - useful in breast cancers, lymphomas, leukemias

Testicular cancer, Sarcomas, Lung cancer

note: the reactive intermediate (acrolein) can be modified with MESNA

It supplies the Thiol group that binds to the reactive intermediate of Ifosfamide (acrolein) and inactivates it.

It is fat soluble so it crosses the BBB and is thus a good treatment in Melanoma and Brain tumors.

• -Streptozocin- plays a role in Islet cell tumors.
• -DTIC- used in melanoma and ABVD protocol for hodgkins
• - Procarbazine- used in hodgkins and brain tumors