8 - Cell Cycle Non-Specific Drugs II Flashcards
Cisplatin:
(cis-diamminedichloroplatinum)
fam, biochem, admin, mech
- fam: metal compound, an older drug
- biochem: amino groups are on the same side (cis-conformation), –> charged due to electronegativity
- admin: Intravenous
- mech:
- alkylates DNA –> forms intrastrand and interstrand DNA cross-links
- affects replication, transcription, receptor-binding, and blocks the cell –> cell goes into apoptosis
Cisplatin:
indications, toxicity
- indications:
- advanced testicular cancer - combination therapy w/ bleomycin, etoposide, vinblastine
- ovarian cancer - comb. therapy w/ paclitaxel
- synergizes w/ alkylating agents (fluoropyrimidines and taxanes)
- toxicity: (nasty drug, but it works)
- acute: nausea and vomiting
- chronic:
- nephrotoxicity (major concern, hydration recommended)
- peripheral sensory neuropathy
- ototoxicity (toxic to the ear (oto-), specifically the cochlea or auditory nerve and sometimes the vestibular system)
- nerve dysfunction
synergism: define
(w/ regard to drugs)
- An interaction between two or more drugs that causes the total effect of the drugs to be greater than the sum of the individual effects of each drug
- can be beneficial or harmful
what is the key concept w/ regards to intraperitoneal therapy?
sometimes new therapeutic concepts don’t work; difficult and nearly 50% of pt’s discontinued therapy
(in theory, it was to tx ovarian cancer and seek to maximize the drug effect;
since intraperitoneal to plasma concentrations inc > 100)
Transplatin:
biochem, mech
- biochem: trans amino groups
- mech: ineffective as cancer chemotherapeutic agent –due to kinetic instability
- alkylating agent that DOESN’T modify critical lesions
- DNA adduct profile is different from cisplatin
- good example (a small change in structure can have great effect on activity)
Carboplatin:
biochem, mech, indication, toxicity
- biochem:
- second-gen platinum analog (advanced form of drug and better design)
- NH3 groups still in cis-conformation
- mech:
- cytotoxic action (alkylating agent) – mechanisms of resistance
- clinical pharm is identical to those of cisplatin
- indications:
- broad-spectrum, for wide range of solid tumors
- toxicity:
- **main dose-limiting toxicity is myelosuppression
- exhibits sig. less renal, GI, and ototoxicities
Carboplatin:
clinical pharmacology
- used in transplant mech to tx refractory hematologic malignancies
- **intravenous hydration is NOT REQUIRED for this therapy bc it’s simplified and LESS NEPHROTOXICITY results
- easier to administer to patients
- replaces Cisplatin in various combination chemo regimens
Oxaliplatin:
biochem, mech, indications, toxicity
- biochem: 3rd gen diaminocyclohexane platinum analog
- advanced form of drug – better design
- amino groups still in cis conformation (coordinate bond)
- mech:
- identical to that of cisplatin and carboplatin
- indications: (used if CA wasn’t cured w/ another drug)
- FOLFOX regimen –> for advanced colorectal cancer, and adjuvant therapy for stage III colon CA and high-risk stage II colon cancer
- (Folinic acid, 5-Fluorouracil, Oxaliplatin)
- pancreatic CA, gastroesophageal, hepatocellular CA
- FOLFOX regimen –> for advanced colorectal cancer, and adjuvant therapy for stage III colon CA and high-risk stage II colon cancer
- toxicity:
- neurotoxicity (*dose-limiting toxicity)
- manifested by peripherap sensory neuropathy
- 2 forms of neurotoxicity:
- acute: triggered and worsened by exposure to cold
- chronic: dose-dependent and reversible
what is the FOLFOX regimen?
-
Name:
- FOL = folinic acid (leucovorin)
- F = 5-fluororuacil (5-FU)
- OX = oxaliplatin
- Tx of:
- advanced colorectal cancer
- adjuvant therapy of stage III colon cancer, and high risk stage II colon cancer
Arsenic trioxide:
biochem, mech, indicated, toxicity
- biochem: electronegative molecule; identified/extracted as active ingredient from chinese herbal medicine
- mech:
- induces differentiation and apoptosis
- (induces the tumor cells to “reverse back” into normal cells (reverses carcinogenesis)
- indications:
- used for tx of acute promyelocytic leukemia
- toxicity:
- Lightheadedness during infusion
- fatigue
- musculoskeletal pain
- hyperglycemia and peripheral neuropathy
due to the side effects of Arsenic trioxide, what is an important part of past medical history to know about the patient?
Need to know if the patient is diabetic bc the drug causes HYPERGLYCEMIA
Antiestrogen therapy:
overview of theory and mechanism
- antagonists of estrogen receptors are available, w/ mixed agonist/antagonist properties
- selective estrogen receptor modifier (Tamoxifen) –> used as 1st line therapy for hormonal tx of breast CA
Tamoxifen:
biochem, mech, admin, indicated, toxicities
- biochem: nonsteroidal agent
- mech:
- **competitive inhibitor of estradiol binding to the estrogen receptor –> induces conformational change/ selectively modulating estrogen receptor –>
- inhibiting binding of estrogen response element on DNA
- admin: orally, prescribed for 5 yrs (due to risk of 2° uterine tumors)
- indications:
- adjuvant therapy for early breast CA –> 35% dec in contralateral breast CA
- toxicity:
- hot flashes
- N/V
- weight gain
- endometriosis
- blood-clotting abnormalities
- depression, tiredness, dizziness
why is St. John’s Wort contraindicated w/ a drug like Tamoxifen?
The OTC medicine (St. John’s Wort) acts on topoisomerase II – inhibits cancer chemotherapy because it also binds competitively to Topoisomerase II
Aromatase:
define, location
an enzyme which produces estrogen from androgens;
estrogen synthesis occurs in the ovary and in adrenal gland;
after menopause, synthesis only occurs in adrenal gland
aromatase inhibitors:
biochem, mech, indication & examples, toxicity
- biochem: nonsteroidal drugs which inhibit aromatase
- e.g. Anastrozole, Letrozole
- mech: prevents conversion to estrone and estradiol
- indication: starting to replace tamoxifen in breast CA tx in many postmenopausal women
- toxicity: not as severe as tamoxifen
Describe the rxn of estrogen receptors and cell pharmacology/pathology
tamoxifen:
- pharmacological antagonist
- Cell can become resistant to Tamoxifen if increased estrogen (competing it out);
- mutation – cancer is constantly changing; you want to minimize drug resistance
- organism (cancer cell) is adapting to it’s environment and mutate the receptor
How does the Aromatase inhibitors affect the mechanism of estradiol synthesis?
prevents estradiol synthesis –> preventing effects of the binding b/w estradiol and estradiol receptors
