Pharm II (chemo 1b)

• 1. Bone marrrow suppression
• 2. Vessican properties
• 3. Hemorrhagic Cystitis
• 4. Secondary Malignancies

• - interstial fibrosis
• - procarbazine
• - antabuse effect

• 1. alkyl group is reactive
• intermediate of all alkylating agents

• 2. cell cycle non-specific
• (sometimes called radiomimetic)

3. most are vesicants

• 4. broad range of use
• particularly H.D., non-hodgkin’s lymphoma, and breast cancer

5. myelosuppression is most common dose-limiting toxicity

• 1. Most active during DNA synthesis
• 2. Inhibit DNA, RNA, and protein synthesis
• 3. First family of rationally designed
• chemotherapy agents

• 1. anti-folates eg. Methotrexate
• 2. pyrimidine analogues eg. 5-FU, ARA-C
• 3. purine analogues eg. 6-MP, 5-TG
• 4. urea analogues eg. hydroxyurea

1.thymidylate synthetase (makes Thymine) requires reduced folate

2. DHFR is an enzyme that is required to convert oxidized folate to reduced folate

• 3. methotrexate is similar to oxidized folate and
• competes with oxidized folate for access to DHFR --> thus inhibiting Thymine production.

• Not metabolized
• Slightly acidic (soluble in Basic enviroments)
• Does not Cross the BBB

The Cancer cells

• - increased production of DHFR
• (gene amplification)
• - decreased affinity of DHFR for MTX
• (mutation)
• - decreased drug uptake (gene amplification)

• - bone marrow suppression
• - skin rashes
• - mucositis
• - hepatotoxicity
• - pulmonary toxicity

• It collects in pleural effusions and ascitic fluid
• it is slowly released from there mimicking a slow infusion of the drug.
• This is called 3rd spacing

• 1. cancer cells have higher GF
• than non-cancer cell population
• 2. methotrexate is more activein higher GF cell population
• 3. may rescue Normal tissue with lower GF cell population with excess reduced folate by increaseing 5-FU toxicity.
• 4. dangerous and timing is critical

• PRIMARY ACTION
• 1. 5-FU converted to (f-dump)
• 2. 5f-dump competes with dump for Thymidylate Synthase--> inhibits DNA synthesis

• SECONDARY ACTION
• 1. 5F-UMP incorporated into RNA and acts as false pyrimidine

In FUNGAL CELLS It can also be converted to 5f-dump--> inhibiting TS--> inhibiting DNA synthesis.

• 1. decreased activation of 5-FU
• 2. increased activity of TS
• 3. reduced drug sensitivity of enzyme

Adding reduced folate, this creates an additional bond between the 5-fdump and the TS.

Colorectal, Breast and GI cancers

• GI
• Skin - (sun sensativity and venous discoloration)
• Myelosuppression

• It is a prodruge that is converted to 5-FU in the liver
• It mimics the action of 5-FU
• Toxicity is HAND AND FOOT SYNDROME

• 1. incorporated into DNA
• 2. inhibits DNA polymerase
• 3. inhibits DNA elongation

• 1. increased activity of cytidine deaminase (inactivates it)
• 2. decreased activity of deoxycytidine kinase (activates the drug)
• 3. decreased affinity of DNA polymerase for ARA-C

AML

• 1. severe BM suppression
• 2. GI
• 3. unusual neuro toxicity (Cerebellar dysfunction)

1. cytosine analogue that is structural similarities to ARA-C

2. key drug in treatment of pancreatic cancer

6 MP and 6 TG

• They are substrates of HGPRT (enzyme that salvages Purines for later use).
• They are converted to False Purines (6 Thio GMP) and (6 Thio IMP)
• They are incorportated and inhibite DNA synthesis. Attach the 1st commited step of DNA synthesis

• 1. metabolized to deoxynucleotides and incorporated into DNA.
• 3. active during DNA synthesis - inhibit it

• 1. decreased activity of HGPRT
• 2. increased drug degradation

Leukemias

- D/ N / V

Decreases activity of 5-FU by inhibiting PRPP which is needed to convert 5-FU to 5-Fdump

- increases activity of purine analogs Because PRPP is needed to incorporate them into DNA

• 1. analogue of urea
• 2. inhibits ribonucleotide reductase that converts RNA to DNA and thus inhibits DNA synthesis.

• - methotrexate
• - pemetrexed
• - raltitrexed

• - 5-FU
• - capecitabine
• - (pemetrexed)

• - ARA-C
• - gemcitabine
• - (fludarabine)

• - hydroxyurea
• - (fludarabine)

• cell cycle specific
• has a unique target
• toxicity of - myelosuppression and GI