Medical Pharmacology Chapter 33-34:  Anticancer Drugs

• Alkylating Agents:

  • Classification: Platinum Analogs:

    • Oxaliplatin (Eloxatin): Overview

      • Oxaliplatin (Eloxatin)

      • 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 (V_d) 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.

    • Adverse Effects:

      • 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.

             

            • Adjuvant treatment for colon cancer (Oxaliplatin and 5-FU (5-fluorouracil):  How to treat a stage III colon cancer? (Reducing Neuropathic Toxicities)

              Attribution: Cervantes A Adjuvant treatment for colon cancer:  How to treat a stage III colon cancer" https://www.youtube.com/watch?v=zjJiUS6sH64 ESMD (European Society for Medical Oncology) Youtube Channel:  https://www.youtube.com/channel/UC7SPyIzaAkrzTS1hmQoa-1g

      • 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

        • "Reducing the neurotoxic side effects of adjuvant chemotherapy for colon cancer"⁹

          Attribution: Arkenau H-T Reducing the neurotoxic side effects of adjuvant chemotherapy for colon cancer. https://www.youtube.com/watch?v=QN5oZgZogss  (6/2017) VJOncology Youtube Channel https://www.youtube.com/channel/UCn3u5oMgE00_qIex2IzGjYg