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what are the platinum cmpds drugs?
- Cisplatin (Platinol)
- Carboplatin (Paraplatin)
- Oxaliplatin (Eloxatin)
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which drug is a Derivative of cisplatin, Causes more myelosuppression, Less nephrotoxicity, neurotoxicity, ototoxicity, nausea, and vomiting?
Carboplatin (Paraplatin)
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plat cmpds MOA:
cross-link DNA strands, thereby inhibiting DNA synthesis and function
-
plat cmpds indication?
Cancers of the testes, ovary, bladder, head and neck, lung, esophagogastric, and colorectal cancer
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SE of plat cmpds?
- N/V- severe
- Nephrotoxicity
- myelosuppression
- tinnitus & hearing loss
- peripheral neuropathy - features cold intol
- hyperuricemia
- hypersensitivity
-
which drug is nephrotox and peripheral neuropathy (cold intol) seen with?
- Nephrotox= cisplatin
- cold intol= oxaliplatin
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plat cmpds mech of resistance:
- DNA repair mechanisms
- Overexpression of Efflux transporter:
- Copper efflux transporters·
- Results in more drug being pumped out of the cancer cell·
- Increased chance of therapeutic failure
-
Emetogenicity of parental chemotherapeutic drugs-
high:
moderate:
- High: Carmustine, Cisplatin
- Moderate: Cabazitaxel, Carboplatin, Oxaliplatin
-
Testicular CA regime:
Bleomycin, Etoposide, CISplatin. (BEP)
-
Non-small cell lung CA regime:
- PACLItaxel, CARBOplatin-
- Gold standard –( platinum doublets)
-
Small cell lung CA regime:
CARBOplatin, Etoposide
-
Ovarian CA regime:
- PACLItaxel, CARBOplatin
- #1 regime to use
-
what are the taxanes?
- Naturally derived
- Work by inhibiting mitosis
-
Taxane drugs:
- Paclitaxel (Taxol®)
- Docetaxel (Taxotere®)
- Cabazitaxel (Jevtana®)
- Nanoparticle albumin-bound (nab) paclitaxel (Abraxane®)
-
Taxane MOA:
- Microtubules perform several important functions in the cell, the key being the segregation of chromosomes during mitosis
- The taxanes are microtubule inhibitors
-
Taxanes indications:
- Cancers:
- Breast
- Ovary
- Lung
- Head and neck
- Prostate (hormone-refractory)
- Pancreatic (off-label)·
- (nab) paclitaxel
- Prevention of restenosis after angioplasty
-
SE of taxanes:
- neurotoxicity- on exam
- myelosuppression
- resistant fluid retension
- hypersensitivity (c/ infusion)
-
which taxane tends to produce the most edema?
Docetaxel
-
which drug is most likely to cause hypersensitivity c/ infusion?
Paclitaxel
-
mech of resistance for taxanes?
- Increased expression of MDR efflux pumps
- Tumor cells can overexpress a mutated isoform of β-tubulin·
- Prevents binding of taxanes
- Vinca alkaloids may be able to bind the mutated β-tubulin
-
Head and neck CA regime:
CISplatin, hydration
-
Prostate CA regime:
DOCEtaxel (1st line for metastatic-on exam), PredinoSONE
-
Non-small cell lung CA regime when plat doublet fails:
DOCEtaxel- for palliative care
-
Breast CA regime:
- PACLtaxel – highest med for sensitivity during infusion- on exam
- AC: Doxorubicin, cyclophosphamide, then give -> PACLtaxel, give Herceptin if HER + (on exam)
-
Ovarian CA regime:
PACLtaxel, CARBOplatin
-
Non-small cell lung CA regime- 2nd line for metastatic-
on exam
DOCEtaxel
-
Non-metastatic testicular CA Tx:
surgery
-
Steps for testicular CA tx:
on exam
- 1. Surgery on prostate OR radiotherapy on prostate
- 2. Androgen deprovation… medical castration OR chemical (testosterone < 50)
- 3. DOCEtexal + predinSONE
-
Supportive care to reduce sensitivity:
- H2 antagonist, H1 antagonist, & dexamethasone
-
what are the Topoisomerase Inhibitors?
- Derived from natural sources
- Exert their cytotoxic effects by interfering with DNA
- Similar mechanism to that of the fluoroquinolone antibiotics
-
Topoisomerase Inhibitors drugs:
- Camptothecins
- Topotecan (Hycamtin®)
- Irinotecan (Camptosar®)
- Podophyllotoxins
- Etoposide (VePesid®)
- Teniposide (Vumon®)
-
Topoisomerase Inhibitors MOA:
- Topoisomerase is an enzyme that cuts and reseals DNA strands, a process that is essential for DNA synthesis
- Topoisomerase inhibitors block the resealing step, leading to large amounts of fragmented DNA.
-
Topoisomerase Inhibitors kinetics-
Topotecan:
Irinotecan:
- All are available in intravenous formulations
- Oral dosage forms: Etoposide and topotecan
- Topotecan: elim 1/2 life= 2-3 hrs, renally
- Irinotecan: liver, The parent is metabolized by CYP3A4·
- It has an active metabolite (SN-38)
- Has much greater antitumor activity than the parent compound
- Metabolized by glucuronidation via UGT1A
-
Indications for
Topotecan:
Irinotecan:
- Topotecan: Cancers of the ovary, Lung (Small cell)
- Irinotecan: Colorectal cancer, Pancreatic CA
-
Indications for
Etoposide:
Teniposide:
- Etoposide: Lymphoma, Cancers of the lung, testes- 1st line for testicular CA
- Teniposide: Neuroblastoma, Non-Hodgkin's lymphoma, Acute lymphocytic leukemia
-
Topo iso CI:
specifically for Topotecan:
specifically for Irinotecan:
- Pregnancy and lactation
- Topotecan: Severe bone marrow suppression, Severe renal impairment
- Irinotecan: Concomitant administration of potent CYP3A4 inhibitors such as ketoconazole
- Can lead to significantly increased toxicity
- Severe leukopenia, thrombocytopenia
- Significant hepatic and/or renal impairment
-
SE (general):
Irinotecan:
Etoposide, Teniposide:
- general: N/V/ alopecia
- Irinotecan: is a cholinesterase inhibitor
- diarrhea- early onset can be managed c/ atropine. Late onset (can be life threatening) treated with Loperamide (Imodium)
- Etoposide, Teniposide: Hypersensitivity and anaphylaxis, Transient hypotension
-
Serious SE of topo iso?
- Bone marrow suppression
- May lead to severe neutropenia, thrombocytopenia, and/or anemia
- Interstitial lung disease (Potentially fatal)
- Cough, fever, dyspnea, and/or hypoxia
- Topotecan > irinotecan
-
Pharmacogenetics for topo iso?
- UGT1A1*28 polymorphism (this is a genetic test, measure it in someone using irinotecan, if they have UGT1A1 polymorphism they have greater risk of fatal hematologic tox)
- Seen in approximately 10% of North Americans
- Patients will have decreased ability to metabolize SN-38 (active metabolite of irinotecan)
- Greater risk of serious toxicities
- Fatal hematologic toxicities
- Neutropenia
-
mech of resistance for topo iso?
- Inadequate accumulation of drug in tumor
- Alterations in the topoisomerase binding
- Altered cellular response to formation of DNA fragments ·
- Enhanced expression of antiapoptotic proteins such as bcl-2
-
2nd line Ovarian CA regime:
Topotecan
-
2nd line Small cell lung CA regime:
Topotrcan
-
Colon CA regime: (Neoadujuvant= before surgery)
- Irinotecan, Leucovorin, Fluorouracil, Bevacizumab (FOLFIRI)- 2nd line
- MFUL FOX 6 is 1st line
-
Diffuse Large B-cell lymphoma regime, 1st line for pt with poor left ventricular function?
Rituximab, Cyclophosphamide, Etoposide,VinCRIStine, PredniSONE (RCEOP)
-
How do the Vinca Alkaloids work?
work by inhibiting mitosis
-
vinca Alkaloid drugs:
- Vincristine (Oncovin ®) – used in R-CHOP for non-hodgkin lymphoma
- Vinblastine (Velban®)
- Vindesine (Eldisine®)
- Vinorelbine (Navelbine®)
-
MOA for vinca alkaloids:
- The vinca alkaloids bind β-tubulin which inhibits its polymerization into microtubules resulting in prevention of spindle formation in dividing cells.·
- Microtubule is the structure of the cell
-
Indication for vinca alkaloid:
- Leukemias
- Lymphomas
- Testicular cancer
-
Indication for Vinorelbine:
-
CI for vinca alkaloids:
- Neurologic diseases·
- Particularly vincristine
- Intrathecal administration
- Intrathecal route is fatal- on exam
- Severe bone marrow suppression
- With vinblastine
- Pregnancy
-
SE for vinca alkaloids:
on exam
- Myelosuppression
- Peripheral neuropathy
- Nausea, vomiting, and alopecia
- Extravastion (Vesicant)
- Occur when infusions leak into the skin·
- Injections are mistakenly given by the intramuscular or subcutaneous route
-
which vinca alkaloid drug is least likely to cause bone marrow suppression?
- Vincristine
- why it’s a preferred agent for R-CHOP regime
- Useful in combination regimens in treating leukemia and lymphoma
-
which vinca alkaloid has least neurotox?
Vinblastine
-
which is Intermediate in terms of both bone marrow suppression and neurotoxicity?
Vinorelbine
-
mech of resistance for vinca alkaloid?
- Increased drug efflux through the Pgp transporter·
- Mutations in β-tubulin- Prevent binding of drug
-
3rd line tx for Testicular CA:
VinBLAStine, Mesna, Ifosfamide, CISplastin, hydration (VeIP)- 3rd line
-
1st line for hodgkins lymphoma:
ABVD
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2nd or 3rd line for Small cell and non-small cell lung CA regime:
VinORELBine – palliative care, not an attempt for cure
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