Platinum cmpds, Taxanes, Topoisomerase inhibitors, Vinca Alkaloids
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what are the platinum cmpds drugs?
- Cisplatin (Platinol)
- Carboplatin (Paraplatin)
- Oxaliplatin (Eloxatin)
which drug is a Derivative of cisplatin, Causes more myelosuppression, Less nephrotoxicity, neurotoxicity, ototoxicity, nausea, and vomiting?
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
SE of plat cmpds?
- N/V- severe
- tinnitus & hearing loss
- peripheral neuropathy - features cold intol
which drug is nephrotox and peripheral neuropathy (cold intol) seen with?
- Nephrotox= cisplatin
- cold intol= oxaliplatin
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: 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:
Ovarian CA regime:
- PACLItaxel, CARBOplatin
- #1 regime to use
what are the taxanes?
- Naturally derived
- Work by inhibiting mitosis
- Paclitaxel (Taxol®)
- Docetaxel (Taxotere®)
- Cabazitaxel (Jevtana®)
- Nanoparticle albumin-bound (nab) paclitaxel (Abraxane®)
- Microtubules perform several important functions in the cell, the key being the segregation of chromosomes during mitosis
- The taxanes are microtubule inhibitors
- Head and neck
- Prostate (hormone-refractory)
- Pancreatic (off-label)·
- (nab) paclitaxel
- Prevention of restenosis after angioplasty
SE of taxanes:
- neurotoxicity- on exam
- resistant fluid retension
- hypersensitivity (c/ infusion)
which taxane tends to produce the most edema?
which drug is most likely to cause hypersensitivity c/ infusion?
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:
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:
Non-small cell lung CA regime- 2nd line for metastatic-
Non-metastatic testicular CA Tx:
Steps for testicular CA tx:
- 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:
- Topotecan (Hycamtin®)
- Irinotecan (Camptosar®)
- 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-
- 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
- Topotecan: Cancers of the ovary, Lung (Small cell)
- Irinotecan: Colorectal cancer, Pancreatic CA
- 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
- 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
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:
2nd line Small cell lung CA regime:
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:
- 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
SE for vinca alkaloids:
- 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?
- 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?
which is Intermediate in terms of both bone marrow suppression and neurotoxicity?
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:
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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