Medical Pharmacology Chapter 33-34: Anticancer Drugs
Classification: Platinum Analogs:
Oxaliplatin (Eloxatin): Overview
Oxaliplatin is a third-generation platinum analogue (diaminocyclohexene).3
However, with respect to mechanism of action and clinical pharmacology this agent appears identical to cisplatin and carboplatin.
Importantly, however, some tumors resistant to cisplatin or carboplatin, due to mismatch repair defects, do not show cross-resistance to oxaliplatin.
This finding may be the basis of the clinical observation that oxaliplatin exhibits activity in colorectal cancer.3
Initial approval of oxaliplatin was as a second-line treatment in combination with 5-FU (fluoropyrimidine 5-fluorouracil) and leukovorin for metastatic colon cancer.3
This protocol was referred to as the FOLFOX regimen.3
In various formulations of FOLFOX, this intervention is a first-line treatment for advanced colorectal cancer.
The regimen is also important in stage III colon cancer in an adjuvant role as well as in high-risk stage II colon cancer.
Oxaliplatin exhibits clinical activity another gastrointestinal cancers such as pancreatic.
The primary dose-limiting toxicities neurotoxicity presenting as peripheral sensory neuropathy.3
The neurotoxicity presents both as an acute form which is worse and then triggered by cold exposure and a chronic form that appears dose-dependent.3
Mechanism of Action:
Cisplatin (Platinol), as well as carboplatin and oxaliplatin initiate their cytotoxic activity by first entering cells by means of a high affinity Cu2+ CTR1 transporter.1
Degraded transporter activity is associated with transporting these agents.
The compounds are extruded from cells by other copper transporters, in this case exporters.1
These "exporters" are ATP7A and ATP7B.
Clinical resistance to the action of these platinum-based antineoplastic drugs depends in part on the expression level of these transporters.
Once inside the cell, specific ligands associated with the platinum drugs are displaced by water which results in a positively charged molecule, highly reactive with DNA and proteins.1
Cisplatin is perhaps the most prominent organoplatinum anticancer agent.
Formation of DNA-platinum adducts inhibit both transcription and replication.1
Oxaliplatin interacts with DNA mainly in interstrand cross-linking with diguanosine dinucleotides as well as with adjacent adenine-guanine nucleotides as well as with guanines separated by one nucleotide (G-X-G).7
Less commonly, interstrand cross-linking also occurs.7
Adduct formation between DNA diguanosine dinucleotides and oxaliplatin appears structurally i.e. conformationally different from adducts formed with cisplatin or carboplatin. 7
The conformation of the oxaliplatin-DNA adduct appears to be less easily recognized by mismatch repair (MMR) proteins.
As noted above, oxaliplatin is effective in tumors otherwise resistant to the effects of cisplatin or carboplatin due to mismatch repair defects.7
These adducts induce single-and double-stranded breaks as well as miscoding.
If the adducts in DNA are so recognized by p53 and other checkpoint proteins, programmed cell death or apoptosis is induced.
Various platinum analogues are different with respect to adduct configuration and adduct effects on DNA structure and function.1
For example, carboplatin (Paraplatin) and oxaliplatin (Eloxatin) form adducts more slowly compared to cisplatin.
Absorption, distribution, Metabolism Excretion:
Oxaliplatin exhibits a relatively short t1/2 in plasma (initial t1/2 is about 15 min.).1
Both chemical reactivity and tissue uptake of oxaliplatin contribute to the short t1/2.1
Oxaliplatin volume of distribution (Vd) is about 440 L.9
This drug is extensively protein-bound (>90%) mainly with albumin and gamma globulin.
Oxaliplatin is sensitive to rapid and extensive nonenzymatic metabolism which results in both inactive and active derivatives.
About 50% of the platinum is excreted in the urine (approximately 2%).9
Some Clinical Uses:
Oxaliplatin exhibits antitumor activity including colorectal and gastric cancer which is different from other platinum drugs.
Effectiveness in colorectal cancer may be due to its MMR-and HMG-(Mismatch Repair; High Mobility Group) independent effects.
Oxaliplatin also suppresses thymidylate synthase (TS) which is the target enzyme of the antineoplastic agent 5-fluorouracil (5-FU).
Oxaliplatin in combination with 5-FU, has been approved for therapy of patients with colorectal cancer.
Peripheral neuropathy represents the dose-limiting oxaliplatin toxic effect.1
One form develops acutely, triggered by cold liquids, and presents as parasthesias and dysesthesias in the mouth, throat and upper and lower limbs.
The other manifestation develops with cumulative dose and exhibits features comparable to that observed with cisplatin neuropathology.
These features include a progressive sensory neurotoxicity including dysesthesias, extremity numbness and ataxia.
Oxaliplatin is associated with mild to moderate hematological toxicity with the exception of rare immune system mediated cytopenias.1
In the long-term oxaliplatin administration may cause leukemia and pulmonary fibrosis in a time frame extending months to years after drug administration.
Acute allergic responses to oxaliplatin include hypotension, bronchoconstriction, and hives.1
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