Anticancer Drugs Flashcards
What are three confounding factors making chemotherapy more difficult?
Tumor doesn’t idle between doses - it seeks to repopulate, But patient needs time to recover
Tumor not homogenous - cells on surface grow faster, must penetrate
Tumors develop resistance over time - multiple drug resistant pump exports variety of drugs
What does it mean that cell kill with chemotherapy is first order?
Fixed percentage of cells can be killed with cancer drug per dose
Also called logarithmic kill
What are anti metabolites? What is their major use?
Analogs of purines or pyrimidines or corresponding nucleosides
Many are pro drugs
Inhibit DNA polymerase or cause chain termination
Some inhibit synthesis of bases or nucleosides directly
Major use is leukemia and lymphomas
Fluorouracil (5FU) - mechanism of action
Activated to 5-FdUMP which mimics dUMP, the substrate for thymidylate synthase, which synthesizes thymidine nucleotides
Thymidine levels drop and cells in s phase killed
Nucleotides derived can also incorporate into DNA or RNA
Fluorouracil - adverse effects
Bone marrow depression
Oral and GI ulcers
Fluorouracil - therapeutic uses
Pancreatic cancer and other adenomas
Cytarabine - mechanism of action
Cytosine analog
Converted to triphosphate, incorporates into DNA, and inhibits chain elongation
Cells exposed in s phase die - block between g1 and s
Cytarabine - therapeutic uses
Single most important agent for AML
Methotrexate - mechanism of action
Analog of folic acid
Binds to mammalian DHFR and inhibits it - depletes building blocks for DNA and RNA synthesis and buildup of toxic product
Cells in s phase most sensitive
Methotrexate with leucovorin
Normal cells exposed to high dose methotrexate can be rescued by leucovorin if given within 36 hrs - a folate coenzyme
Methotrexate - adverse effects
Myelosuppression and GI ulceration
*Pneumonitis
Methotrexate - therapeutic uses
Leukemias
Choriocarcinoma and other neoplasms
Anti inflammatory
Methotrexate - resistance
Caused by amplification of DHFR gene
DNA alkylating agents - mechanism of action
Contain chemical groups that can cyclize to generate positively charged reactive intermediates that can be attacked by lone pair of electrons on nitrogen or oxygen
Result is alkylation of DNA and cross linking of strands
Toxic - don’t discriminate between cancer and normal cells
Phase nonspecific but cells don’t die until they enter s phase
Cyclophosphamide
Alkylating agent - nitrogen mustard
Oral and inactive until pass through liver and activated by p450 oxidase - easier to administer and less toxic
*Can irritate bladder causing hemorrhagic cystitis - avoid dehydration
Alkylating agents - adverse effects
Bone marrow suppression
GI ulcers
Alkylating agents - therapeutic uses
Leukemias and solid tumors
Cisplatin - mechanism of action
Platinum complex alkylating agents
Bifunctional - react with guanines on same or different DNA strands
Water replaces chlorides creating carbonium ions that are attacked by N7 of guanine bases
Cisplatin - adverse effects
Ototoxicity and peripheral neuropathy
*Renal toxicity if dehydrated
Nausea and vomiting
Myelosuppressive
Cisplatin - therapeutic uses
Solid tumors - particularly testicular and ovarian
Mechlorethamine
Nitrogen mustard alkylating agent
Anthracyclines - mechanism of action
Antibiotics produces by a fungus
Tetracycline ring that can intercalate into DNA
Can be reduced within cells generating semiquinones that autoxidize and generate reactive oxygen radicals
Cause DNA strand breaks by radical damage or interfering with topoisomerase type II
Anthracyclines (doxorubicin) - adverse effects
*Unique cardiomyopathy - usually irreversible, happens with cumulative overdose
Dose dependent
Doxorubicin
Anthracycline
Major use in carcinomas of breast, ovary, uterus, testicle, and lung, and for many sarcomas
Bleomycin - mechanism of action
Chelates iron and copper and binds to DNA
Leads to toxic radicals that cause strand breaks and chromosomal aberrations
Concentrates in late s and g2 - g2 specific agent
Bleomycin - adverse effects
Not toxic to bone marrow
*Pulmonary fibrosis
Various skin conditions inc hyper pigmentation and ulcers
Bleomycin - therapeutic uses
Effective against germ cell tumors of testes and ovary and for squamous cell carcinomas
Irinotecan - mechanism of action
A camptothecin
Bind and inhibit topoisomerase I
Results in first single stranded DNA breaks then double strand during s phase when DNA polymerase collides with drug enzyme complex
S phase specific
Metabolized to SN-38 - elim by glucoronidation by UGT1A1
Irinotecan - side effects
Nausea
Leukopenia
Patients with less active UGT1A1 more susceptible
Irinotecan - uses
Several solid tumors, particularly ovarian, lung, breast, and colorectal cancer
Etoposide
Epipodophyllotoxin
Bind and inhibits topoisomerase II leading to DNA breaks
Useful against leukemias and lymphomas
Vinca alkaloids (vincristine, vinblastine)
Bind tubulin alpha beta dimers and prevent formation of MTs
M phase specific
Myelosuppressive and neurotoxic
*peripheral neuropathy
Where is vincristine used vs. vinblastine?
Vincristine - childhood leukemias and lymphomas
Vinblastine - testicular cancer and other solid tumors
Paclitaxel
A taxane
Bind to existing MTs and inhibits disassembly which inhibits mitosis
Effective for breast and ovarian cancers
Prednisone
Glucocorticoid
Great for leukemias
Better response in children
Resistance quickly unless other drugs used together
Tamoxifen
Selective estrogen receptor modulator - binds competitively
Treatment of breast cancer - only tumors with this receptor respond
Prophylactic treatment in women at high risk
Better response in post menopausal women w/ lower estrogen
Hot flashes often accompany first use
Anastrozole
Nonsteroidal reversible inhibitor of aromatase
Aromatase catalyzes conversion to estrogen in peripheral tissues in post menopausal women
Useful for estrogen sensitive breast tumors
Flutamide
Anti androgen
Treatment for prostate cancer
Combo with GnRH agonist to cause chemical castration
Leuprolide
GnRH agonist
Cause transient release of FSH and LH followed by feedback inhibition to cease testosterone production
Treatment of prostate cancer
Combo with flutamide to block effect of initial FSH/LH surge
Bevacizumab
Monoclonal antibody that binds to and inhibits VEGF
Colorectal, breast, and lung cancer (but not breast anymore)
Side effects are increased bleeding and slow wound healing
What type of cancer has interleukin-2 been approved for?
Malignant metastatic melanoma
Appears active for other tumors and leukemias
Bortezomib
Inhibits proteosome
I-kappaB degradation allows NF-kappaB to migrate to nucleus and activate genes but this degradation doesn’t happen now
Tretinoin (ATRA)
Binds to RAR and displaces transcription inhibitor to promote differentiation
Treats APL
ATRA syndrome - pulmonary infiltration causing inflammation and *respiratory distress, can be prevented by adding glucocorticoids
Thalidomide
Role in inhibiting angiogenesis and stimulating immune system
Imp in treatment of multiple myeloma
Blocking of TNF and VEGF pathways and prevents production of il-6 which normally promotes adhesion of tumor cells to bone marrow stroma
How are colony stimulating factors used in the treatment of cancer?
Increase number of normal blood cells
Epo, granulocytes colony stimulating factor and granulocytes-macrophage colony stimulating factor all available
What is one combination of drugs given commonly but limited in dose due to overlapping toxicities?
Cyclophosphamide and doxorubicin
What is the primary treatment for brain metastases and why?
Radiation
Most chemotherapy doesn’t cross BBB
What is dose dense treatment?
Admin of same doses and number of cycles of chemotherapy but over shorter time
Combine with growth factor support to maintain blood counts at acceptable range
What is one drug that is synergistic with irinotecan?
5-fluorouracil
