Pharm Lecture 55 Anti-Neoplastics

Front 1

Mechlorethamine

Back 1

Class 1, alkylating nitrogen mustard.
Mech: nucleophilic attack on DNA, RNA, proteins. Crosslinks (bifunctional) & breaks.
Use: IV, no CNS. HL & NHL. T1/2=secs.
Resistance: less entry, more nucleophiles.
ASE: myelosuppression (indicator of effectiveness), GI damage, n/v, alopecia.

Front 2

Carmustine

Back 2

Class 1, alkylating nitrosurea.
Mech: nucleophilic attack on DNA, RNA, proteins. Crosslinks & breaks.
Use: IV, lipophilic (CNS). Brain tumors, mult myeloma, melanoma.
Resistance: less entry, more nucleophiles.
ASE: myelosuppression (indicator of effectiveness), GI damage, n/v, alopecia.

Front 3

Prednisone

Back 3

Class 2: G1 Phase. Adrenocorticosteroid.
Mech: binds steroid receptor, depresses RNA synthesis for growth genes, induces nucleases (cell lysis).
Use: anti-emetic, palliative therapy (appetite, sense of well-being, anti-inflammatory). Leukemia, lymphoma, breast.
ASE: little myelopsuppression.

Front 4

Cytarabine

Back 4

Class 2: S Phase. Antimetabolite, pyrimidine analog.
Cytosine arabinoside (cytidine analog). Competes w/cytidine: 3 phosphorylation steps & dCTP into DNA. Also induces tumor cell differentiation.
Use: IV. Acute leukemias.
Biphasic renal excretion.
ASE: myelosuppression, neurotox.

Front 5

Fluorouracil

Back 5

Class 2: S Phase. Antimetabolite, pyrimidine analog.
Activated to FUTP (inhibits RNA) & FdUMP (inhibits thymidylate/DNA).
Use: IV, Colon & breast, topical for BCC. Broad spectrum.
Liver metabolism, renal & pulm. excretion (as CO2).
ASE: n/d, anorexia, myelosuppression.

Front 6

Methotrexate

Back 6

Class 2: S Phase. Antimetabolite, folate analog.
Mech: binds DHFR, prevents THF synthesis (& thymidine synthesis).
Use: oral/IV high dose, no CNS, rescue w/leucovorin. ALL, choriocarcinoma.
ASE: drug interaction w/agents that bind albumin (displacement), GI, BM suppression, renal tubular necrosis (renal excretion, need to alkalinize urine).

Front 7

Mercaptopurine

Back 7

Class 2: S Phase. Antimetabolite, purine analog.
Converted to ribonucleotide, inhibits RNA/DNA synthesis.
Use: oral, acute leukemias.
Extensive liver metabolism, renal excretion. Inactivated by thiopurine methyltransferase (genetic defects).
ASE: BM depression, n/v, anorexia, liver damage (jaundice).

Front 8

Hydroxyurea

Back 8

Class 2: S Phase. Antimetabolite, substituted urea.
Inhibits ribonucleotide reductase, blocks DNA synthesis, arrests cell at G1/S interface (radiosensitive). Impairs DNA repair.
Use: oral, enters CNS. Granulocytic leukemia, head/neck cancer.
ASE: hematopoietic depression, GI.

Front 9

Bleomycin

Back 9

Class 2: G2 Phase. Natural antibiotic.
Mech: glycopeptides bind DNA. Oxidative damage, breaks.
Use: broad spectrum.
ASE: pulm. toxicity (pneumonitis, fibrosis, dose-related), skin vesiculation & hyperpigmentation. Little BM suppression.

Front 10

Etoposide

Back 10

Class 2: G2 Phase, epipodophyllotoxin (mandrake).
Mech: stabilizes DNA/topoisomerase II, breaks.
Use: IV, broad spectrum.
Renal excretion.
ASE: leukopenia, n/v/d, alopecia.

Front 11

Paclitaxel

Back 11

Class 2: late G2 phase (G2/M interface: radiosensitive). Natural taxane (yew).
Mech: binds tubulin beta-subunit, stabilizes microtubules, blocks disassembly. Blocks DNA repair.
Use: refractory ovarian cancer, breast.
ASE: leukopenia (limits dose), peripheral neuropathy, myalgia/arthralgia.

Front 12

Vinblastine

Back 12

Class 2: M phase. Natural vinca alkaloid (periwinkle).
Binds tubulin (blocks assembly), cells arrest in metaphase.
ASE: strongly myelosuppressive, epithelial ulcers.

Front 13

Vincristine

Back 13

Class 2: M phase. Natural vinca alkaloid (periwinkle).
Binds tubulin (blocks assembly), cells arrest in metaphase.
ASE: alopecia, neuromuscular (incl. peripheral neuropathy). Little BM suppression.

Front 14

Procarbazine

Back 14

Class 2: G1 & S phases. Methylating agent.
Prodrug.
Mech: adds methyl, damages DNA.
Use: HL & NHL.
ASE: myelosuppression, n/v.

Front 15

Cyclophosphamide

Back 15

Class 3, alkylating nitrogen mustard.
Mech: nucleophilic attack on DNA, RNA, proteins. Crosslinks & breaks.
Activated by liver CYP450.
Use: IV or oral, no CNS. Broad spectrum.
Resistance: less entry, more nucleophiles.
ASE: sterile hemorrhagic cystitis (acrolein), myelosuppression (indicator of effectiveness), GI damage, n/v, alopecia.

Front 16

Cisplatin

Back 16

Class 3, metal salt, platinum coordination complex.
Mech: crosslinks DNA, causes kinks & breaks. Reacts w/thioredoxin reductase, promoting apoptosis.
Use: broad spectrum, testis & ovary.
ASE: nephrotoxicity, ototoxicity, peripheral neuropathy, electrolyte disturbance, n/v (100%), myelosuppression.

Front 17

Doxorubicin

Back 17

Class 3, natural antibiotic.
Mech: intercalates (blocks DNA/RNA synthesis), lipid peroxidation, free radicals, binds DNA/topoisomerase II (prevents DNA resealing), blocks blood vessel formation.
Use: broad spectrum.
ASE: dilated cardiomyopathy, BM suppression, alopecia, GI.

Front 18

Filgrastin

Back 18

Biological response modifier, recombinant protein.
Mech: G-CSF. Stimulates PMN production by BM.
Use: IV, SC. Given after myelopsuppressive agents.
ASE: bone pain.

Front 19

Trastuzumab

Back 19

Monoclonal antibody.
Binds HER2 (epidermal growth factor) receptor.
Use: breast cancers that overexpress HER2.
ASE: cardiomyopathy, hypersensitivity (incl. anaphylaxis), infusion rxn.

Front 20

Tamoxifen

Back 20

Anti-estrogen, non-steroidal receptor antagonist.
Activated by CYP2D6 (genetics).
Measure estrogen receptors in biopsy 1st.
Stops cell growth, gets cells into G0, no killing.
Use: post-menopause & pre-menopause (w/mets) BC treatment. BC prophylaxis.
ASE: hot flashes, fatigue, n/v, musculoskeletal pain. No osteoporosis.

Front 21

Letrozole

Back 21

Anti-estrogen, non-steroidal aromatase inhibitor (all tissues).
Inhibits growth, no killing. No inhibition of adrenal steroid synthesis.
Use: 1st line for BC in post-menopause.
ASE: musculoskeletal pain, hot flashes, nausea, fatigue, osteoporosis.

Front 22

Leuprolide

Back 22

Anti-androgenic, synthetic GnRH analog.
Initial increase in LH/FSH (disease flare). Inhibits LH/FSH secretion in 2-4 weeks.
Use: 1st line for advanced hormonally-responsive prostate cancer. Monthly subcutaneous.
ASE: hot flashes, impotence.

Front 23

Flutamide

Back 23

Anti-androgenic, non-steroid receptor antagonist.
Use: oral, metastatic prostate cancer in combo w/GnRH analog (blocks disease flare).
Rapid metabolism, renal excretion.
ASE: gynecomastia, diarrhea, hepatotoxicity.

Front 24

Principles of combination chemotherapy

Back 24

1. Agents that act against various cell types (cell cycle specific & non-specific).
2. Active as single agents.
3. Non-overlapping toxicities.
4. Optimal dose & schedule.
5. Consistent intervals.
6. Diff. mech's to minimize resistance.

Front 25

Categories of combination chemotherapy

Back 25

1. Sequential blockade: same path.
2. Concurrent inhibition: 2 paths.
3. Complementary inhibition: affect synthesis & end product.
4. Rescue: leucorvorin, BM transplant.
5. Synchronization: cells in 1 phase.
6. Recruitment: cells into cycle from G0.