Classical Anti-Neoplastics

Methotrexate, 5-FU, 6-MP

Anti-Metabolites (3)

Etoposide

Topoisomerase Inhibitors (1)

Cyclophosphamide, cisplatin

Alkylating Agents (2)

Doxorubicin, bleomycin

Antibiotic Agents (2)

Vincristine, paclitaxel

Microtubule Inhibitors (2)

Leucovorin, mesna

Rescue agents for anticancer drugs - (2)

DNA, apoptosis, narrow

Challenges with anticancer drugs

• Most are anti-proliferative (i.e. damage __) and initiate __

• Anticancer drugs have a __ therapeutic window/therapeutic index

Hair follicle, bone marrow, sperm forming, GI mucosa

Rapidly dividing normal cells - (4)

Bone marrow, GI, hair follicles, gonads, 1st

Common side effects with anti-cancer drugs

• __ __ - leukopenia, immuno-suppression, thrombocytopenia, anemia

• __ - oral and intestinal ulceration, diarrhea

• __ __ - alopecia

• __ - Impaired spermatogenesis, infertility

• Teratogenic (especially in __ trimester)

Therapeutic Window

Minimum effective concentration to minimum toxic concentration

TD50/ED50

Therapeutic Index formula

Etoposide

S2 and G2 acting

Bleomycin

G2 phase acting

Vincristine and paclitaxel

M phase acting

Methotrexate, 5-FU, 6-MP

S phase acting

Cyclophosphamide, cisplatin, doxorubicin

Cell-cycle non-specific or G0

Methotrexate (MTX)

Inhibits dihydrofolate reductase (DHFR) interfering with synthesis of tetrahydrofolate

THF

Coenzyme involved in de novo synthesis of thymidine, purine ring, and amino acids serine and methionine

DNA, RNA, proteins, human DHFR

Methotrexate (MTX)

• Inhibition of these processes interferes with formation of __, __ and key cellular proteins

• MTX is too toxic to use as antibiotic due to inhibiting __ __ as well pathological

Bone marrow, megaloblastic anemia

Methotrexate Adverse Effects

• __ __ suppression

• __ __ (from folic acid deficiency)

Leucovorin

Folinic acid serving as a rescue agent of MTX toxicity

5-Fluorouracil (5-FU)

Converted to 5-FdUMP that competitively inhibits thymidylate synthase

Thymidineless, FdUTP, FUTP, DNA, RNA, leucovorin

5-Fluorouracil (5-FU)

• Causes __ death of cells

• Active compounds (__ and __) are incorporated into both __ and __, inhibiting their functions

• Commonly combined with __ (drug) to increase efficacy and stability of 5-FU

Hand and foot, bone marrow

Adverse Effects of 5-FU

• __ and __ syndrome

• __ __ depression

6-Mercaptopurine (6-MP)

Inhibits the synthesis of purines

Purine, RNA, DNA, pro-drug

6-Mercaptopurine (6-MP)

• Incorporate into RNA and DNA for __ synthesis → non-functional __ and __

• Is classified as a ___

Bone marrow depression

Adverse Effect of 6-MP - (1)

Etoposide

Inhibits topoisomerase II causing DNA replication inhibition and damage

Bone marrow depression

Adverse Effects of Etoposide - (1)

Alkylating Agents

Covalently alkylate N7 on guanine and crosslink DNA

Cyclophosphamide

__ (cyclophosphamide/cisplatin) is a pro-drug that covalently alkylate N7 on guanine

Hemorrhagic cystitis from acrolein

Adverse Effect of Cyclophosphamide

MESNA

Binds to and inactivates toxic metabolite acrolein to prevent hemorrhagic cystitis from cyclophosphamide

Nephro, creatinine, GFR, oto, less

Adverse Effects of Cisplatin

• __toxicity

  • Elevated __ (lab) and Reduced __ (function)

• __toxicity

• __ bone marrow suppression

Doxorubicin

Block RNA and DNA synthesis and cause strand scission

Base pairs, topoisomerase II, free radicals

Doxorubicin

• Intercalating between __ __

• Inhibiting __ __ (enzyme)

• Generating __ __ for damage to DNA

Cardiac, cardiomyopathy, failure

Adverse Effects of Doxorubicin

• __ toxicity from free radicals - acute

• Dilated __ - chronic

• Heart __ - chronic

Bleomycin

Binding to DNA and induce single and double-strand breaks

Free radical, synthesis

Bleomycin

• __ __ formation for DNA damage

• Inhibition of DNA __

Pulmonary, less

Adverse Effects of Bleomycin

• __ fibrosis

• __ bone marrow suppression

Mitosis

Vincristine and paclitaxel inhibit…

Vincristine

Blocking formation of mitotic spindle by preventing assembly of tubulin dimers into microtubules

Peripheral neuropathy, less

Adverse Effects of Vincristine

• __ __

• __ bone marrow suppression

Paclitaxel

Inhibits microtubule disassembly into tubulin monomers

Peripheral neuropathy only

Adverse Effects of Paclitaxel - (1)