Term
| what are the acute side effects associated with antineoplastics? |
|
Definition
1)bone marrow toxicity - inf./hemorrhage
2)GI mucosa toxicity - diarrhea
3)Hair follicle toxicity- hair loss
4)Germline cell toxicity - infertility |
|
|
Term
| what are the chronic side effects associated with antineoplstics? |
|
Definition
cardiomyopathy
neurotoxicity
GI tract distress
nephrotoxicity
mutagenesis
carcinogenesis |
|
|
Term
| why do antineoplastics have limited effectiveness? |
|
Definition
1)they only target cells in the cell cycle/proliferating
2)cells become resistant to therapy after rounds of chemo |
|
|
Term
| why do antineoplastics have limited effectiveness? |
|
Definition
1)they only target cells in the cell cycle/proliferating
2)cells become resistant to therapy after rounds of chemo |
|
|
Term
| how do alkylating agents work? |
|
Definition
| they alkylate DNA leading to cell death |
|
|
Term
| How do antimetabolites work against cancer? |
|
Definition
| they inhibit RNA and DNA function |
|
|
Term
| what is the most toxic way that alkylating agents work? |
|
Definition
| crosslinking BETWEEN DNA strands |
|
|
Term
| what is the mechanism of mechloraethamine? |
|
Definition
alkylation within DNA at N7 of guanine
BIFUNCTIONAL AGENT |
|
|
Term
| what are the side effects of mechloraethamine? |
|
Definition
nausea and vomiting
STRONG VESICANT |
|
|
Term
| what are the mechanisms of resistance to mechloraethamine? |
|
Definition
1)*DECREASED ACTIVE TRANSPORT - required for drug to get into cell
2)increased gluthione
3)increased DNA repair |
|
|
Term
| what are the used of mechloraethamine? |
|
Definition
1)combo therpy for Hodgkins' (MOPP)
2)cutaneous T cell lymphoma |
|
|
Term
| what is mechanism of action of cyclophosphamide? |
|
Definition
alkylation of DNA
*requires metabolism by CYP2B |
|
|
Term
| what are the side effects of cyclophosphamide? |
|
Definition
bone marrow insufficiency
**alopecia
**hemorrhagic cystitis |
|
|
Term
| what is the mechanism of action of Melphalan? |
|
Definition
| alkylation within DNA at N7 on guanine |
|
|
Term
| what is important about the side effects of Melphalan? |
|
Definition
1)No alopecia or changes in renal/hepatic function at standard dose
2)Less freq. nausea and vomiting compared to other alkylating agents |
|
|
Term
| How is resistance developed to Melphalan? |
|
Definition
| decrease in active transport |
|
|
Term
| Busulfan is a ________ agent |
|
Definition
|
|
Term
| what are the side effects of Busulfan? |
|
Definition
skin pigmenation - appear as freackles but get larger/darker
pulmonary fibrosis
adrenal insufficiency |
|
|
Term
| what is Nitrosureas used to treat? |
|
Definition
|
|
Term
| what is the only alkylating agent that can cross the BBB? |
|
Definition
|
|
Term
| what is the Carmustine Wafer? |
|
Definition
| implanted in patients to help treat high grade gliomas |
|
|
Term
| what is the target of Nitrosureas? |
|
Definition
alkylation of O6 gunanine leading to G-C crosslinks
BIFUNCTIONAL alkylating agent |
|
|
Term
| what is responsible for resistance to Nitrosureas? |
|
Definition
increased AGT activity
*decreased in 30% of primary gliomas so sensitive to treatment |
|
|
Term
| what phase of the cell cycle is highly targeted by antimetabolites? |
|
Definition
| S phase- where DNA is synthesized |
|
|
Term
| what antimetabolite is a folate antagonist? |
|
Definition
|
|
Term
| what is the mechanism of methotrexate? |
|
Definition
| folic acid analog which reversibly inhibits dihydrofolate reductase resulting in decreased dTMP |
|
|
Term
| what all does methatrexate cause decreased production of? |
|
Definition
| adenine, guanine, thymidine, methionine, serine |
|
|
Term
| what is the most prominent use of Methotrexate? |
|
Definition
| Burkitt's lymphoma in kids |
|
|
Term
| what are most drug interaction with methotrexate due to? |
|
Definition
| its high affinity for plasma albumin |
|
|
Term
| what are the side effects of methotrexate? |
|
Definition
bone marrow suppression
GI
alopecia
dermatitis
**NEPHROTXICITY - use leucovorin rescue!! |
|
|
Term
| what should be used with methotrexate to help with nephrotoxicity? |
|
Definition
|
|
Term
| what is responsible for resistance to methotrexate? |
|
Definition
1)impaired active transport
2)reduced affinty of DHFR
3)increased conc. of DHFR
4)**decreased ability to synthesize METHOTREXATE POLYGLUTAMATES
5)increased MDR protein |
|
|
Term
| what does leucovorin bypass? |
|
Definition
|
|
Term
| what does 6-Mercaptopurine inhibit the synthesis of? |
|
Definition
|
|
Term
| what is the first enzyme that acts on 6-mercaptpurine when it enters the cell? |
|
Definition
| HGPRT - very imp bc can be up/downregulated very quickly |
|
|
Term
| what is an important drug interaction with 6-mercaptopurine? |
|
Definition
| allopurinol -used for gout/hyperuricemia |
|
|
Term
| Fludarabine is a ________ analogue |
|
Definition
|
|
Term
| what are the side effects of Fludarabine? |
|
Definition
**TUMOR LYSIS SYNDROME
myelosuppression, nausea, vomiting |
|
|
Term
| Name 3 purine antagonists |
|
Definition
6-mercaptopurine
6-thioguanine
fludarabine |
|
|
Term
| what is tumor lysis syndrome? |
|
Definition
*side effect of fludarabine
hyper - kalemia, uricemia, phosphatemia
hypo - calcemia
results in acute renal failure |
|
|
Term
| what is the mechanism of 5-fluorouracil? |
|
Definition
| pyrimidine analog that inhibits thymidylate synthetase, thus preventing synthesis of thymidylic acid needed for DNA synthesis |
|
|
Term
| what is the cause of resistance to 5-fluorouracil? |
|
Definition
| altered/increased thymidylate synthase |
|
|
Term
| what is the clinical use of 5-fluorouracil? |
|
Definition
1)leukemia
2)***solid tumors such as breast, GI, ovary, bladder - even whhen alot of cells not in the S phase |
|
|
Term
| what is the mechanism of Capecitabine? |
|
Definition
| hydrolyzed to 5-FU by thymidine phosphorylase which is concentrated in tumor cells |
|
|
Term
| In what phase of the cell cycle are cytidine analogs such as Ara-C most toxic? |
|
Definition
|
|
Term
| what is the mechanism of Ara-C, cytidine analog? |
|
Definition
| terminatees DNA chain elongation - only works in the S phase |
|
|
Term
| what is the clincal use of Ara-C, cytidine analogs? |
|
Definition
acute myelogenous leukemia
**single most effective agent for induction of remission in AML |
|
|
Term
| what is the mechanism of Gemcitabine, cytidine analog? |
|
Definition
terminates DNA chain elongation and inhibits ribonucleotide reductase
**toxicity NOT confined to S phase!! |
|
|
Term
| when is Gemcitabine contraindicated? |
|
Definition
| should NOT be used with radiotherapy - it sensitizes all your cells to radiotherapy so cells get damaged that normally wouldn't |
|
|
Term
| Name 4 pyrimidine antagonists |
|
Definition
5-FU
capectibine
cytarabine (C-Ara)
gemcitabine |
|
|
Term
| where does Mitomycin C come from? |
|
Definition
| Streptococcus caespitosus |
|
|
Term
| what is the mechanism of Mitomycin C? |
|
Definition
| undergoes metabolic activation t become an alkylating agent that cross-links DNA |
|
|
Term
| what type of tumors does Mitomycin C work best in and why? |
|
Definition
| **hypoxic tumors due to the chemical necessity for reduction to its active metabolite - important bc core of tumors is usually a hypoxic environment |
|
|
Term
| what are the side effects of Mitomycin C? |
|
Definition
| **Hemolytic Uremic Syndrome due to damage to endothelium |
|
|
Term
| what phases of the cell cycle are most sensitive to Etoposide? |
|
Definition
|
|
Term
| what is the mechanim of Etoposide? |
|
Definition
| **forms a ternary complex with topoisomerase II**and DNA to prevent resealing of the break that normally follows topoisomerase binding to DNA |
|
|
Term
| what is a side effect seen in patients that were treated with Etoposide for childhood ALL? |
|
Definition
| increased incidence of acute nonlymphcytic leukemia |
|
|
Term
| what is the clinical use of Etoposide? |
|
Definition
**Kaposi's sarcoma**
tesicular tumor
small cell carinoma of lung |
|
|
Term
|
Definition
| it is a natural product that inhibits topoisomerase I and is S-phase specific |
|
|
Term
| what is the mechanism of Topotecan? |
|
Definition
| inhibits topoisomerase I - leads to accumulation of single-stranded breaks |
|
|
Term
| what is a side effect of Topotecan? |
|
Definition
|
|
Term
| what results in resistance to Topotecan? |
|
Definition
1)decreased intracellular accumulation
2)P-glycoprotein
3)decreased expression or mutation of topoisomerase I
4)exposure to topoisomerase-I inhibitors leads to increased expression of topoisomerase II |
|
|
Term
| what is the current treatment of choice for colorectal cancer? |
|
Definition
|
|
Term
| what is the active metabolite of Irinotecan? |
|
Definition
| Irinotecan is a prodrug - must be metabolized into **SN-38 |
|
|
Term
| what is the mechanism of Irinotecan? |
|
Definition
|
|
Term
| How is Irinotecan cleared? |
|
Definition
1)**carboxylesterases in the liver
2)**hepatic metabolism via CYP3A |
|
|
Term
| what are the side effects of Irinotecan? |
|
Definition
|
|
Term
| what is NOT repsonsible for resistance to Irinotecan that causes resistance in Topotecan? |
|
Definition
|
|
Term
| Tamoxifen is used to treat what type of breats cancer? |
|
Definition
| estrogen receptor positive |
|
|
Term
| prostatic carcinoma is dependent on stimulation with _________ |
|
Definition
|
|
Term
| what type of therpy is used for advanced prostae cancer? |
|
Definition
|
|
Term
| what three hormones are used to treat prostate cancer? |
|
Definition
Leuprolide
Goserelin
Flutamide |
|
|
Term
| what is the mechanism of Leuprolide and Goserelin? |
|
Definition
| GnRH agonists that result in initial surge of LH/FSH but then cause the inihibiton of gonadotropin release causing testosterone production to decrease to castration levels |
|
|
Term
| when is Leuprolide and Goserelin use contraindicated? |
|
Definition
| during pregnancy - can stimulate abortion |
|
|
Term
| Flutamide has less ________________ than steroid blockers |
|
Definition
|
|
Term
| what are the side effects of Flutamide? |
|
Definition
**severe liver damage*
gynecomastia, weightt loss, loss of muscle mass, vasomotor flushing |
|
|
Term
| what is Flutamide used to treat? |
|
Definition
|
|
Term
| what two drugs are often given together for prostate cancer? |
|
Definition
|
|
Term
| what phases of the cell cycle are most vulnerable to Cisplatin/Carboplatin? |
|
Definition
|
|
Term
| what is the mechanism of Cisplatin/ Carbaplatin? |
|
Definition
bind N7 guanine and form inter and intrastrand cross-links
*inhibit DNA rep. and RNA synthesis |
|
|
Term
| what does L-asparginase inhibit |
|
Definition
|
|
Term
| what are the side effects of Cisplatin? |
|
Definition
| nephrotoxicity, ototoxicity, and neurotoxicity |
|
|
Term
| what side effects are NOT seen with Carboplastin that are seen when taking Cisplatin? |
|
Definition
| nephro- neuro- and ototoxicity |
|
|
Term
| What makes cells resistant to Cisplatin and Carboplatin? |
|
Definition
| increased levels of metallothionein which bind to and inactivate both drugs |
|
|
Term
| what can help ameliorate nephrotoxicity when taking Cisplatin? |
|
Definition
| aggressive hydration and diuresis |
|
|
Term
| what is the mechanism of hydroxyurea? |
|
Definition
| inhibits ribonucleoside diphosphate reductase which catalyzes the reduction conversion of ribonucleotides to deoxyribonucleotides |
|
|
Term
| what phase of the cell cycle is hydroxyurea specific for? |
|
Definition
|
|
Term
| what is the clincal use of hydroxyurea? |
|
Definition
1)It potentiates the activity of other DNA damaging drugs such as cisplatin, alkylating agents, topo-II inhibitors and facilitates incoporation of drugs sucha as Ara-C, gemcitabine or fludarabine into DNA
2) it has been placed into several treatment schedules because of its ability to synchronize cells in the radiosensitive portion of the cell cycle |
|
|
Term
| what is the mechansim of action of L-asparaginase? |
|
Definition
catalyzes the deamination of asparagine to aspartic acid and amonia
***some neoplastic cells require an external source of asparagine and this drug metabolizes blood asparagine thus limiting availability for tumor cells |
|
|
Term
| what is the mechanism of Imatinib? |
|
Definition
| tyrosine kinase inhibitor |
|
|
Term
| Imatinib is inhibitory against ________ in CML |
|
Definition
|
|
Term
| what is Imatinib used to treat? |
|
Definition
|
|
Term
| what are the side effects of L-asparaginase? |
|
Definition
1)hypersensitivity reactions because it is a foreign protein (derived from bacteria)
2)coma due to ammonia toxicity |
|
|
Term
| what is the mechanism of Gefinitib? |
|
Definition
| inhibits EGFR tyrosine kinase - arrests cells at G0/G1 |
|
|
Term
| what is the predominate problem for resistance seen to Gefinitib? |
|
Definition
| *low response rate* - poor tumor penetration, drug efflux, mutations affecting drug sensitivity |
|
|
Term
| what is the clincal use of Gefinitib? |
|
Definition
| non small cell lung cancer in patients that failed standard therapy |
|
|
Term
| High expression of EGFR (epidermal growth factor receptor) is generally associated with ? |
|
Definition
| a poor outcome (i.e. invasion, metastasis, late-stage disease, chemo resistance, hormone-therapy resistance) |
|
|
Term
| Gefinitib is a __________ inhibitor. |
|
Definition
|
|
Term
| what is the mechanism of Bevacizumab? |
|
Definition
| antiangiogenic - humanized monoclonal antibody against VEGF that prevents interaction with its receptors |
|
|
Term
| what is the clinical use of Bevacizumab? |
|
Definition
| colorectal cancer (along with 5-FU) |
|
|
Term
| what are the side effects of Bevacizumab? |
|
Definition
hemorrhage, GI perforation
**severe hypertension, proteinuria, CHF** |
|
|
Term
| what is the clincal use of Thalidomide? |
|
Definition
|
|
Term
| what are the possible mechanisms of Thalidomide? |
|
Definition
(1)inhibition of NFκB or Bcl-2 family members -promoting apoptosis
(2) inhibition of cytokine production -antiangiogenic
(3) immunomodulatory effects |
|
|
Term
| In tumor vascular development, angiogenesis is 3 stages |
|
Definition
1)Initiation
2)proliferation
3)migration and invasion |
|
|
Term
| Name three anti-angiongenic drugs |
|
Definition
1)Bevacizumab
2)Thalidomide
3)Sunitinib |
|
|
Term
| Sunitinib inhibits what two receptors? |
|
Definition
|
|
Term
| Sunitinib inhibits what two receptors? |
|
Definition
|
|
Term
| what is the mechanism of action of cyclosporine? |
|
Definition
| *binds cyclophilin* - forms a complex that binds calcineurin |
|
|
Term
| What is the primary result of cyclosporine use? |
|
Definition
|
|
Term
| what is the primary result of cyclosporine? |
|
Definition
|
|
Term
| What are the side effects of cyclosporine? |
|
Definition
|
|
Term
| what are the four categories of immunosuppressives? |
|
Definition
1)glucocorticoids
2)calcineurin inhibitors
3)antiproliferative/antimetabolic agents
4)biologics |
|
|
Term
| Inhibition of CYP 3A by _____________ has a big effect on cyclosporine levels in the body. |
|
Definition
|
|
Term
| What is the main clinical use of cyclosporine? |
|
Definition
1)mainly organ transplantation including: kidney, liver, heart
2)rheumatoid arthritis
3)psoriasis |
|
|
Term
| what is the mechanism os Tacrolimus? |
|
Definition
| binds to the immmunophilin, FKBP-12 and inhibits calcineurin |
|
|
Term
| what are the side effects of Tacrolimus? |
|
Definition
**diabetes
nephro and neurotoxicity |
|
|
Term
| What is the mechanism of action of azathioprine? |
|
Definition
| It is a prodrug that is converted to 6-MP so it acts as a purine antagonist |
|
|
Term
| what is the clinical use of Tacrolimus? |
|
Definition
| used as rescue therapy in patients with rejection episodes despite therapeutic levels of cyclosporine |
|
|
Term
| Azathiopurine is best used for what kind of immune response? |
|
Definition
| it is most useful for an acute immune response and has little effect on chronic immune responses |
|
|
Term
| Name two calcineurin inhibitors |
|
Definition
|
|
Term
| Azathioprine actually works better than 6-MP which may reflect ____________________. |
|
Definition
| better drug uptake or pharmacokinetic profile |
|
|
Term
| Azathiopurine interacts with what other drug? |
|
Definition
|
|
Term
| what is the effect of GM-CSF? |
|
Definition
| stimulates myelopoiesis - produced naturally by endothelial cells, macs, and Tcells |
|
|
Term
| what is the effect of G-CSF? |
|
Definition
| increased neutrophil production and enhanced their phagocytic function |
|
|
Term
| what is the treatment of choice for iron deficiency and prophylaxis during pregnancy? |
|
Definition
|
|
Term
| what is the mechanism of Deferoxamine? |
|
Definition
|
|
Term
| what is contraindicated in oral iron therapy? |
|
Definition
| antacids - prevent absorption |
|
|
Term
| Deficiency of what two things can cause megaloblastic anemia? |
|
Definition
|
|
Term
| what are the 5 alkylating agents that Bauer described? |
|
Definition
1)mechloraethamine
2)cyclophosphamide
3)melphalan
4)busulfan
5)nitrosureas |
|
|
Term
| Name 3 Purine antagonists: |
|
Definition
1)6-mercaptopurine
2)6-thioguanine
3)fludarabine |
|
|
Term
| What is the mechanism of action of 6-mercaptopurine? |
|
Definition
| (structural analog of adenine)It inhibits de novo synthesis of adenine AND guanine |
|
|
Term
| Name the four pyrimidine antagonist: |
|
Definition
1)5-fluorouracil
2)capectibine
3)cytarabine
4)gemcitabine |
|
|
Term
| ____________ is necessary for the maturations and proliferation of t-cells. |
|
Definition
|
|
Term
| Name 2 calcineurin inhibitors: |
|
Definition
1)cyclosporine
2)tacrolimus
(by inhibiting calcineurin, they stop production of IL-2 thus stopping maturation and proliferation of T-cells) |
|
|
