Lecture 3 - Platinums anticancer agents. Flashcards
What kind of cancer is cisplatin used for?
It is effective for ovarian, testicular, uterus, bladder and head and neck cancer.
How does cis-platinum and trans-platinum differ in efficacy?
The Cl ligands in the trans platinum(4.64A) is further apart than in cis platinum (3.29A) and this affect the way the Pt(II) cross link with DNA
The second hydrolysis of the trans platinum is very slow due to the stabilising effect of the new trans oxygen ligand. Therefore the differences in efficacy is due to thermodynamics and kinetic.
Describe the mechanism of action of cisplatinum.
Cis-platinum coordinates with the DNA throught the N7 of guanines which form a 1, 2-intrastrand cross links. The DNA structure is disrupted and inhibited from replication and transcription which leads to apoptosis.
Give a brief summary of the physiology of cisplatin.
It is given intravenously into the blood stream, it crosses the cell membrane where it is activated by hydrolysis. It then bind to the DNA. Per 10000 active molecules, only one binds to the cancer cell DNA. The rest causes the side effects.
How is cisplatin administered?
It is given in 250 to 1000ml normal saline mixed with 2-4 grams of MgSO4. It is infused for over 2 hours. 250-1000ml of normal saline may be given as pre hydration and post hydration as well. Instruct the patient to drink 1.5 to 2 liters of water a day.
Some patient may require furosemide.
List the types of toxicity associated with use of cisplatin.
Haematological toxicity
Ototoxicity ( caution with aminoglycosides)
Neurotoxicity
Nephrotoxicity (pre hydration and magnesium supplement)
Nausea and vomiting (anti emetic given)
Give a brief overview of the activation of carboplatin and why is it better than cisplatin
Carboplatin reacts with water and chloride ions which open the chelate ring and activate of carboplatin.
Carboplatin has fewer side effects compared to cisplatin and it is effective on many solid tumours. It is moderately emetogenic. Renal impairment and neurotoxicity are rare. Myelosuppression is dose limiting.
In what type of cancer is oxaliplatin used?
It is used in the treatment of metastatic carcinoma of the colon or rectum as a combination with fluorouracil and leucovirin.
What toxicity is associated with the use of oxaliplatin?
It is moderately emetogenic and minimal haematological. There is no case of nephrotoxicity or ototoxicity. There is a mild case of hypersensitivity which can be prevented with slow infusion or use of antihistamine and corticosteroid.
It causes neuropathy which means that patient should avoid cold temperatures in any case.
What are the advantages of satraplatin?
It can be administered orally and it is effective against hormone refractory prostate cancer. The octahedral Pt(IV) is more kinetically inert than the Pt(II). Pt(IV) is readily reduced in vivo to Pt(II) by reductants such as ascorbates or thiols (e.g glutathione, cysteine)
What are the advantages of targeting prostate cancer with targeted nanoparticles with cisplatin?
Prostate cancer is very resistant to cisplatin based chemotherapy. In this case, prostate cancer is targeted with Prostate Specific Membrane Antigen delivered in nanoparticle as a vehicle. A nontoxic Pt(IV) prodrug is is activated by intracellular reduction to Pt(II) to release the cytotoxic cisplatin. This provide a higher selectivity, less resistance and fewer side effects.
What is Lipoplatin?
It is cisplating surrounded by a lipid bilayer conjugated with a PEGylated lipid. This lipid shell camouflage the toxic cisplatin from the macrophages
