cancer chemotherapies 2 Flashcards
what are chromatin modulators?
Topoisomerase inhibitors:
- Camptothecins
- Anthracyclines (doxorubicin)
- Epipodophyllotoxins
- Amsacrine
Microtubule (need to be formed so cells can undergo mitosis) inhibitors:
- Plant alkaloids or synthetic derivatives of naturally occurring alkaloids
- Vinca alkaloids (vincristine)
- Taxanes (paclitaxel)
Doxorubicin MOA
- topoisomerase II inhibitor and can also generate free radicals
- Topoisomerase II → transient ATP hydrolysis- dependent double-strand break, re-ligation of DNA
- Assists with DNA replication and transcription
-intercalates with DNA - binds to and stabilizes topoisomerase II DNA complex to prevent re- ligation of DNA breaks
- generates free radicals that damage DNA
- inhibits DNA replication and transcription
doxorubicin pharmacokinetics, adverse effects and resistance
Administered IV & used for leukemias and lymphomas, bladder, breast, stomach, lung, ovarian and thyroid carcinomas, soft tissue sarcomas and multiple myeloma
Adverse effects:
- cardiomyopathy/heart failure
- bone marrow suppression
- GI disturbances
- alopecia
- rash/swelling of hands and feet
Resistance:
- ↑ efflux via P-glycoprotein in cell membrane -overexpression or mutation of topoisomerase II
A 68-year-old female who has been losing weight and feeling tired for weeks decides to see her doctor when she develops a fever and notices the lymph nodes in her neck are swollen.
The physical exam and blood and urine tests rule out some conditions and infections that could cause the symptoms. No tumours are identified from imaging test, but the lymph node biopsy reveals the patient has an aggressive form of non- Hodgkin’s lymphoma
what are her treatment options?
Treatment: chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone) followed by radiation
Day 1: cyclophosphamide 750mg/m2 IV + doxorubicin 50mg/m2 IV bolus + vincristine 1.4mg/m2 IV bolus (max dose 2mg)
Day 3: prednisone 100mg orally for 5 days.
Repeat each cycle every 3 weeks for 3 cycles. Radiation therapy begins 3 weeks after last cycle
Younger patients may also receive stem cell transplants
3 cycles as above followed by:
Day 1: cisplatin 100 mg/m2 continuous IV over 24 hours
Day 1 to 4: dexamethasone 40 mg
Day 2: cytarabine 2000 mg/ m2 by continuous IV over 12 hours
Repeat each cycle every 3 weeks for 3 cycles – stem cells transplanted during 3 months after treatment
What are microtubule inhibitors?
- Tubulin polymerizes to form mitotic spindles
- Microtubule half-life decreases → spindle dissolves → cell divides
Vincristine: inhibits tubulin polymerization → dysfunctional spindle
Paclitaxel: inhibits tubulin depolymerization → overly stable microtubules → cell cannot divide
what is vincristine pharmacokinetics and resistance?
From the periwinkle plant (vinca rosea)
Administered IV in combination with other drugs to some carcinomas (small cell lung, breast), leukemias, lymphomas and neuroblastomas
Kills cells in M-stage of cell cycle
Resistance
-altered tubulin structure (mutations) -altered expression of tubulin isotypes
- efflux via P-glycoprotein in cell membrane
what is paclitaxel? its moa?
- Derived from Pacific yew
- Kills cells in M-stage of cell cycle
- Primarily used to treat breast, ovarian and non-small cell lung carcinomas and AIDS-related Kaposi’s sarcoma
paclitaxel adverse effects, drug interactions and resistance?
Adverse effects:
- hypersensitivity
- peripheral neuropathy
- bone marrow suppression
- alopecia
- GI distress, anorexia
Drug interactions:
- also metabolized by CYP3A4 (see vincristine)
Resistance:
- altered tubulin structure (mutations)
- altered expression of tubulin isotypes
- ↑efflux via P-glycoprotein in cell membrane
N-acetylcysteine Given IV With Cisplatin and Paclitaxel in Patients With Ovarian Cancer.
Clinical trial proposal:
Cisplatin has shown efficacy in the treatment of subjects with epithelial ovarian cancer. Systemic toxicities associated with cisplatin-paclitaxel include nephro, oto, and nerve toxicities. It may be possible to reduce these toxicities by administering these drugs in conjunction with IV NAC. NAC may reduce cisplatin-paclitaxel related nephro, oto, and nerve toxicities without compromising the effectiveness of the chemotherapy against the ovarian cancer cells. It is possible that this combination of drugs may in the future allow ovarian cancer patients to receive the full series of cisplatin-paclitaxel chemotherapy, with fewer side effects and improved survival.
what are steroid hormones and antagonists used for?
Useful for cancers with steroid hormone- sensitive cells
- must have steroid receptors
- hormone responsive
- homone-dependent
- steroids regulate expression of genes involved in cell growth and proliferation
prednisone moa
- Converted to active form (prednisolone) in liver
- Binds irreversibly to glucocorticoid receptors
- Can induce apoptosis of leukemic and lymphoid cells
what is prednisone used for, its resistance and adverse effects?
- Used for immune and inflammatory suppression in variety of disorders (oral, inhalation, injection)
For cancer – primarily for lymphomas and leukemias
Resistance: - absence or mutation of receptor
Adverse effects: - immunosuppression
- hypertension
- hyperglycemia
-pancreatitis - weakness
- osteoporosis
- mood changes
what is tamoxifen and what is it used for?
SERM: selective estrogen receptor (ER) modulator
- Administered orally, metabolized in the liver (metabolites behave as antagonists and/or agonist of ERs, depending on the target tissue)
- In estrogen-sensitive breast cancer cells - prevents ER-mediated gene expression → ↓tumour growth
- Currently used to treat and prevent estrogen- dependent breast cancer
tamoxifen resistance and adverse effects
Resistance:
- absence or mutation of receptor (in estrogen receptor)
Adverse effects: (similar symptoms to those in menopause)
- hot flashes
- irregular periods
- blood clots
- reduced cognition
- uterine cancer
what do aromatase inhibitors do?
Aromatase inhibitors (eg. anastrozole): also used to treat breast cancer – do not induce uterine cancer
