Classification:

Mustargen: DNA alkylating agent

Mechanism of Action:

1. Spontaneously forms reactive electrophile in aqueous solution -->

2. Reacts with nucleophile, like N7 position of guanine

3. Both ends form same electrophile --> both bind a guanine and cross-link DNA

*Alkylation and cross-linking

Resistance:

Toxicity:

1. Bone marrow depression

2. Male sterility

3. Amenorrhea

Cyclophosphamide

Ifosfamide

Classification:

DNA alkylating & cross-linking agent

Mechanism of action:

1. Activated by hepatic P450 enzymes to form toxic metabolite --> (not toxic by itself)

2. Reactive intermediates are formed:

- inactive metabolites

- active metabolites

3. Phosphoramide mustard is active metabolite

Resistance:

Toxicity:

1. Bone marrow depression

2. Male sterility

3. Amenorrhea

4. Hemhorragic cystitis from acrolein metabolite --> use MESNA (2-mercapto ethane sulfonate)

Classification:

DNA cross-linking agent

Mechanism of action:

1. In H2O, it slowly subsitutes -Cl^- for OH^-

2. Attacks and binds guanine site on DNA

3. Bifunctional, so forms cross-link on DNA

Resistance:

Toxicity:

1.Bone marrow depression

2. Concentrates into kidney --> converts into active form --> renal tubular damage

*Use hydration and diuretics to mitigate

Classification:

Glycopeptide

Mechanism of action:

1. Intercalates with DNA between G/T -->

2. Chelating Fe²⁺ -->

3. In presence of O₂ creates free radicals -->

4. DNA destruction is result

*not toxic in anaerobic enviornment,

Resistance:

Bleomycin hydrolase: not expressed as much in lung and skin.

Toxicity:

1. Pulmonary fibrosis: concentrates in lung

2. Skin changes:

3. Radiation recall: more toxic if prior radiation to chest area

4. Systemic toxicity in association with lymphoma

Classification:

DNA replication mutagen

Mechanism of action:

1. Intercalates within DNA -->

2. Blocks replication & transcription -->

Resistance:

Toxicity:

1. Bone marrow depression

2. Radiation recall

Doxorubicin

Danorubicin

Idarubicin

Classification:

Topoisomerase II inhibitor

Mechanism of action:

1. Bind to DNA/Topo II complex -->

2. Prevents resealing of DNA nicks -->

3. Inhibition of transcription & DNA replication

Resistance:

Toxicity:

1. Bone marrow depression

2. Cardiomyopathy

3. Radiation recall

Classification:

Topoisomerase II inhibitor

Mechanism of action:

1. Binds to DNA/Topo II complex -->

2. Prevents resealing of DNA nicks -->

3. Inhibits transcription/DNA replication -->

4. Causes DNA strand breaks and cell death

Resistance:

Toxicity:

1. Bone marrow depression

Irinotecan

Topotecan

Classification:

Topoisomerase I DNA inhibitor

Mechanism of action:

1. Bind topoisomerase/DNA complex -->

2. Prevents religation -->

3.Inhibition of transcription and DNA replication

Resistance:

Toxicity:

1. Bone marrow depression

*Metabolized via UDP-glucoronosyl transferase 1A1 and patients with mutations are 5-fold more sensitive. FDA approved testing for common mutations.

Classification:

Human DHFR inhibitor

Mechanism of action:

1. Inhibits human DHFR enzyme -->

2. Inhibition of folate synthesis -->

3. Inability to synthesize purine nucleotides

Resistance:

Clinical use:

Used in combination with 5-Fluorouracil

- 5-FU first --> then MTX = antagonism

- MTX first --> (hrs) then 5-FU = synergism

Why?

*5-FU inhibits thymidylate synthetase --> folate is not used as substrate and builds up --> MTX then does not result in inhibition purine & amino acid synthesis due to extra THF

**In reverse, MTX will lower THF levels --> blocks purine synthesis, which in high levels would inhibit phosphorylation of 5-FU to active component --> thus 5-FU is more quickly phosphorylated to inhibit thymidylate synthetase

Toxicity:

1. Bone marrow depression

*Luecovorin is antidote to MTX

Classification:

Transcriptional and DNA replication antimetabolite

Mechanism of action:

1. Taken up into all cells

2. Inhibits thymidylate synthetase +

3. Misincorporation into mRNA -->

4. Inability of cell to replicate

Resistance:

Clinical use:

Used in combination with 5-Fluorouracil

- 5-FU first --> then MTX = antagonism

- MTX first --> (hrs) then 5-FU = synergism

Why?

*5-FU inhibits thymidylate synthetase --> folate is not used as substrate and builds up --> MTX then does not result in inhibition purine & amino acid synthesis due to extra THF

**In reverse, MTX will lower THF levels --> blocks purine synthesis, which in high levels would inhibit phosphorylation of 5-FU to active component --> thus 5-FU is more quickly phosphorylated to inhibit thymidylate synthetase

Toxicity:

1. Bone marrow depression

Classification:

DNA polymerase inhibitor

Mechanism of Action:

1. difluordeoxycytidine is taken into cell -->

2. Inhibition of DNA polymerase

3. Misincorporation

Resistance:

Clinical use:

Toxicity:

1. Bone marrow depression

Classification:

Ribonucleotide reductase inhibitor

Mechanism of Action:

1. Inhibition of taken ribose to deoxyribose

Resistance:

Clinical use:

Toxicity:

1. Bone marrow depression

Classification:

Purine synthesis inhibitor

Mechanism of Action:

1. Interferes with purine biosynthesis -->

2. Cell cycle arrest and apoptosis

Resistance:

Clinical use:

Toxicity:

1. Bone marrow depression

Tamoxifen

Raloxifene

Classification:

Estrogen receptor antagonist

Mechanism of Action:

1. Disrupt production of IGF-1 and TGF-a

2. Decrease production of tissue plasminogen activator (proteases)

3. Decrease laminin receptor production (adherence)

4. Stimulates TGF-B production (repression of cell proliferatin and increase differentiation)

Resistance:

Clinical use:

Toxicity:

1. Hot flashes

2. Increased incidence of endometrial cancer

3. Thromboembolytic events

*Can impede Estrogen activation of genes in breast, but activate estrogen genes in uterus...

New observations: indirect pathway

1. Estrogen receptor doesn't have to bind to ERE and bind to DNA at all --> can bind to other transcriptional factors (fos/jun, Sp-1, NF-kB, etc)

2. Selective Estrogen Response Modulators (SERM) --> depending on ligand that binds, receptor assumes different conformations --> interacts at other ERE or with other transcription factors (complex)

Classification:

GnRH agonist

Mechanism of Action:

1. Agonist of GnRH receptor -->

2. Downregulation of receptors -->

3. Shuts off GnRH to pituitary to produce gonadotropins and steroid hormones

 - LH and FSH is decreased

- Inhibition of testosterone and estrogen

Resistance:

Clinical use:

1. Advanced prostate cancer

2. Pre-menopausal breast cancer

Toxicity:

1. Hormone withdrawal effects

Classification:

CYP19 aromatase inhibitor

Mechanism of Action:

1. Blocks CYP19 aromatase action -->

2. Blocks testosterone conversion to estrogen

Resistance:

Clinical use:

Toxicity:

1. Effects related to estrogen deficiency

Classification:

Enzyme

Mechanism of Action:

1. Degrades asparagine in circulation -->

2. Converts to aspartic acid -->

3. Starve cells of asparagine -->

4. Inhibition of protein synthesis

*some cancer cells do not have Asn synthetase

Resistance:

Clinical use:

Toxicity:

1. Hypersensitivy reactions

Vincristine

Vinblastine

Vindesine

Classification:

Mitotic inhibitor

Mechanism of Action:

1. Interacts with tubulin -->

2. Prevents microtubule polymerization -->

3. Inhibition of mitosis -->

Resistance:

Clinical use:

Toxicity:

1. Bone marrow depression

2. Peripheral neuropathy

Classification:

Mitotic inhibitor

Mechanism of Action:

1. Binds to microtubules -->

2. Stabilizes and prevents depolymerization

Resistance:

Clinical use:

Toxicity:

1. Bone marrow depression

2. Sensory neuropathy (m-tubules are important in nerve transport)

3. Hypersensitivity --> keep epinephrine ready

Classification:

humanized monoclonal antibody

Mechanism of Action:

1. Monoclonal antibody against HER2 (human epidermial growth factor recptor) -->

2. Recruits immune system to take out tumor cells (ADCC)

3. Antibody may  inhibit activity of receptor too...

Resistance:

Clinical use:

Toxicity:

1. Cardiac toxicity

*Worst when combined with anthracycline (doxorubicin)

*Maybe due to targeting ERB2, which is on heart

Classification:

Humanized monoclonal antibody

Mechanism of Action:

1. Monoclonal antibody against VEGF (vascular endothelial growth factor)

2. Angiogenesis is inhibited

Resistance:

Clinical use:

1. Leaves basement membrane behind -->

2. Halting drug leaves vascular scaffold that is re populized -->

3. Benefits may not persist

Toxicity:

1. Hypertension

2. GI perforation

Gefitnib

Erlotinib

Classification:

Epidermal Growth Factor Receptor (EGFR) inhibitor

Mechanism of action:

1. Binds to ATP binding site on kinase -->

2. Inhibits the EGF receptor

*more effective in lung cancer if tumor has activating mutations in EGFR and depends on EGFR for growth.

Resistance:

Clinical use:

Toxicity:

1. Skin problems

Classification:

ABL tyrosine kinase inhibitor

Mechanism of action:

1. Binds to intracellular ABL protein Y kinase -->

2.

Resistance:

Clinical use:

1. CML

2. Gastric cancers

*Does not cure CML, it will reoccur if drug is not taken (due to cancer stem cells)

Toxicity:

1. Fluid retention

1. Cancer cell mutation rate is higher than in normal cells

2. By time cancer is detected, it is probable that some cells are partially or completely resistance to drug.

Mechanisms:

1. Induction of thiol-containing protective proteins that quench alkylating agents

2. Induction of DNA repair enzymes to fix damaged DNA

3. Induction of enzymes that inactivate drugs

4. Induction of glutathione transferases (catalyzes electrophile reaction with glutathione)

5. Increased efflux of drug by cell mediated transporters

6. Amplification of target gene (DHFR in MTX resistance)

7. Mutations in drug target (Y kinase inhibitors)

*Verapamil will block MDR pump

Classification:

Mechanism of action:

1. Inhibotor of xanthine oxidase -->

2. Decreases production of uric acid

Resistance:

Clinical uses:

1. Killing of high number of cancer cells results in release of purines --> uric acid -->hyperuricemia

2. High release of uric acid, potassium, LDH, magnesium and phosphate from lysed tumors

Toxicity:

1. Hypersensitiviy reactions

Classification:

Folate substitute

Mechanism of action:

1. Substitutes for folate in MTX folate starved cells

Clinical Use:

1. Give lethal dose of MTX to get saturation

2. Come along later and give leucovorin to rescue the "normal" cells

Classification:

Hematopoetic growth factor

Mechanism of action:

1. Stimulates neutrophils and eosinophils

2. Rescue of bone marrow depression

*Allows higher dose therapy with reduced risk of infection and toxicity

Toxicity:

1. Mild to moderate bone pain

2. Skin reactions

1. Fertility:

- alkylating agents almost always cause infertility

2. Increased risk of secondary cancers:

- radiation

- alkylating agents

- cisplatin

- topoisomerase inhibitors

Classification:

Monoclonal Ab against CD20

Mechanism of Action:

1. Binds to CD20 (primarily on B-cell surface) -->

2. Fc portion mediates:

 - Antibody dependent cytotoxicity (ADCC)

 - Complement dependent cytotoxicity (CMC)

Resistance:

1. Absent on fully differentiated plasma cells (good thing)

Clinical applications:

1. Hematological neoplasms

2. Autoimmune disease

3. Anti-rejection for organ recipients

Toxicity:

1. Classical through binding ERE

2. Does not need to bind DNA ERE to induce gene expression...Can bind to a number of other transcription factors (fos/jun, Sp1, NF-kB)

3. Rapid response --> membrane bound steroid receptor results in MAPK cascade

*SERMS (selective estrogen response modulators) --> depending on the ligand binding, a particular conformation is adopted --> different genes activated (ERE or binding of other activators)

- other receptors can be approached this way...

*Ligands can have agonist or antagonist properties depending on ER alpha or Beta and tissue complement of co-regulators

1. Inhibit production of prostaglandin and leukotrienes

- induce annexin expression --> inhibits PL-A2 --> prevents release of arahidonic acid --> no precursor from production

2. Alters leukocyte traffic control

*Cause increase in neutrophil circulation (prevents migration out of blood vessels)

- gap junctions are sealed

- neutrophils can't bind endothelium

- changes neutrophil's ability to respond to chemokines

*Interrupt T-cell/macrophage interactions and ability to produce IL cytokines

3. Inhibits leukocyte function

- results in production of IkBa --> binds NFkB and inhibits inflammation

Can mask underlying disease!!!