cancer chemotherapies 1 Flashcards
what is the treatment regimen for cancer chemo?
- Unlikely that there will ever be one single cure. Selection of drug(s) depends on type of cancer and patient.
Treatment Regimen - most often given in combination (synergistic, different mechanisms of action and resistance)
- drugs should be given as frequently and as close to the maximal effective dose as possible → limitation may need to change regimen or dosage
consider factors like dosage, patient and considerations for cancer chemo
Dosage:
- generally based on body surface area -pharmacokinetics, drug interactions and impact on liver, kidney and immune system taken into account
Patient:
- type/stage of cancer
- health of patient (renal/hepatic function, bone marrow reserve, concurrent medical problems) -desire to undergo difficult/dangerous treatment - ability to cope with side-effects
-pre-treatment screening
Considerations:
- long-term gain vs. risk
- probability of successful treatment vs. quality of life
CASE STUDY
A 66-year-old female presents in the ER with chest pains. No cardiac abnormalities detected, and pain appears to be associated with coughing. Persistent cough has been present for weeks but has recently worsened, patient also has a history of recurring chest infections and until recently, smoked one pack/day.
Additional tests including chest x-ray, CT scan with guided biopsy → diagnosis of small cell lung cancer
what is the best treatment option? the cancer was detected again after 18 months what is the treatment then?
Treatment: radiation + chemotherapy (cisplatin + etoposide)
Cancer detected again after 18 months
Treatment: cyclophosphamide + doxorubicin + vincristine
what are the major classes of DNA alkylating agents?
Major classes
- Alkylsulfonates
- Methyl/ethylenimines
- Nitrogen mustards (cyclophosphamide)
- Nitrosoureas
- *Platinum compounds (cisplatin) Triazenes
*technically not alkylating agents but also bind N7 and cross-link DNA
what is the MOA of DNA alkylating agents?
Mechanism of Action: donating alkyl group to DNA group to induce replication of DNA
- transfer alkyl group to cellular constituents -major site in DNA: N7 and/or O6 of guanine -monofunctional (alkylate single DNA strand) or
bifunctional (alkylate at two locations, cross-link) - proliferating cells more sensitive
what is cyclophosphamide? Its adverse effects? Its resistance?
- Most commonly used alkylating agent -pro-drug, administered IV or orally, activated by
cytochrome P450, lipid soluble - broad spectrum: used alone or in combination with other drugs to treat neuroblastomas, lymphomas, leukemias and colon, breast, ovarian, small cell lung and testicular cancers
Adverse effects - less toxic than some alkylating agents (toxic to replicating cells) due to cellular metabolism of aldophosphamide by aldehyde dehydrogenase (ALDH)
- dose-dependent GI disturbances, bone marrow suppression, immunosuppression, hair loss, hemorrhagic cystitis (inflammation of bladder) (acrolein accumulation)
- increased risk of sterility, menopause, cancer
Resistance - reaction with other cellular constituents
- ↑ metabolism (ALDH, GST)
- ↑ DNA repair eg. cancer cells with high levels of O6-methylguanine-DNA methyl-transferase (MGMT) less susceptible
what is cisplatin? its adverse effects? its resistance?
- Inorganic metal: covalently binds N7 and O6 of guanine, also interacts with cytosine and adenine
- Administered IV; Particularly effective for testicular, bladder and ovarian cancer. Also used to treat lymphomas, sarcomas and lung carcinomas
Adverse effects: - bone marrow suppression
- anemia
- GI distress (one of most emetogenic chemotherapies)
- nephrotoxicity
- electrolyte imbalances
- neurotoxicity (hearing loss, peripheral neuropathy)
Cisplatin resistance - ↓ access to DNA (see mechanisms below)
- ↑ DNA repair
what is FY26?
More Powerful Than Cisplatin, Preclinical Cancer Drug Shows
- The cancer drug, FY26, has demonstrated high potency and efficacy compared with cisplatin and other platinum-based chemotherapies, according to a preclinical trial conducted
“It [FY26] is an organo-osmium compound that induces a lethal burst of reactive oxygen species in cancer cells, but not in normal cells, which confers selectivity,”
- experiments consisting of 809 cancer cell lines, demonstrating that FY26 was 49 times more potent than cisplatin.
CASE STUDY
A 36-year-old male went to his family doctor when he noticed an enlarged testicle.
Additional tests including testicular ultrasound, bloodwork to measure levels of tumour markers suggest the lump is cancerous.
Treatment?
Cancer confirmed and has spread to lymph nodes, CT scan and chest x-ray indicates spread to lung what is the treatment then?
- Treatment: surgery to remove testicle and lymph nodes
- Cancer confirmed and has spread to lymph nodes, CT scan and chest x-ray indicates spread to lung
- Treatment: bleomycin, etoposide and cisplatin
what are non-covalent DNA binding agents? their MOA?
- Antibiotics extracted from the soil microbe streptomyces that have anti-tumour activity
- Form tight drug-DNA interactions
Mechanism of Action: - DNA intercalation
- free radical DNA damage
- → DNA unwinding, impaired synthesis, single and double strand breaks
what is bleomycin? its adverse effects? its resistance?
- Forms bleomycin-Fe(II) complex that interacts with oxygen
- Oxidation of complex → free radicals (O2-, ·OH) → DNA strand breakage & damage of other cellular constituents
Administered through variety of routes (IV, IM, SC), typically in combination with other drugs, to treat lymphomas and cervical, ovarian and testicular cancer
Adverse effects - pulmonary fibrosis
- anaphylaxis
- GI disturbances
- alopecia
Resistance:
-↑ DNA repair (common resistance mechanism)
-↑ drug efflux
-↑ expression of antioxidants or bleomycin hydrolase
what is the commonly used regimen of breast cancer chemotherapy that combines three anti-cancer agents?
- Cyclophosphamide, methotrexate & fluorouracil (CMF)
- Commonly used regimen of breast cancer chemotherapy that combines three anti-cancer agents
- Four-week cycle. On days 1 and 8 methotrexate and fluorouracil are given IV. Cyclophosphamide sometimes administered IV in conjunction with these drugs, or is taken as an oral tablet once a day for the first 14 days of each cycle
- Typical treatments involve 6 to 8 cycles
what are antimetabolites and the major classes?
- Affect cell proliferation by interfering with DNA and RNA synthesis therfore, most effective in s-phase of cell cycle
- Interfere with the availability of purines and pyrimidines
Major classes: - Folate antagonists (methotrexate)
- Pyrimidine analogs (5-fluorouracil)
- Purine analogs
- Sugar-modified analogs
Methotrexate MOA
- Enters cell via active transport
- Folic acid inhibitor: structurally similar to folate & binds to dihydrofolate (DHF) reductase
- methotrexate interferes with this process it acts as a competitor to the enzyme
- reduces purine and pyrimidine synthesis therefore affects RNA, DNA and protein synthesis
- methotrexate-polyglutamate (can also act as inhibitors in the cell) metabolites retained in cells to further inhibit RNA/DNA synthesis
pharmacokinetics and mechanisms of resistance
- Usually used in combination with other drugs for a variety of carcinomas, leukemias and lymphomas
- Administered orally or via injection (IV, IM, SC, IT)
Resistance: - ↓cellular uptake (reduced or no uptake of methotrexate)
- ↑ DHF reductase expression
- ↓ binding to DHF reductase
- ↑ efflux
methotrexate adverse effects and drug interactions
Adverse effects:
- bone marrow suppression
- GI distress, alopecia
- liver damage (long-term treatment)
- renal damage (high dose)
Drug interactions: (most occur at elimination stage)
- aminoglycosides ↓ methotrexate absorption
-NSAIDs, penicillins, cephalosporins, cisplatin, probenecid ↓ methotrexate elimination
5-fluorouracil MOA
- Carrier-mediated transport into the cell
- Converted to ribosyl and deoxyrybosyl nucleotide metabolites and incorporated into RNA and DNA (interfering with its synthesis)
- Inhibits thymidylate synthase (TS) →↓ thymidine synthesis → ↓ DNA synthesis
