Medical Pharmacology Chapter 33-34:  Anticancer Drugs

• Alkylating Agents:

  • Classification: Platinum Analogs:

    • Cisplatin:

      • Cisplatin (Platinol)

      • Cisplatin (Platinol) inhibits DNA synthesis.¹⁰

        • Mechanisms of DNA disruption include:

          • Cross-linking

          • Double helix denaturation, and

          • Bnding (covalently) to DNA bases.

      • The cis-isomer is greater than 10 times more cytotoxic compared to the trans- isomer.¹⁰

        • Both isomers cross-link DNA; however, cisplatin (cis-platinum) is less likely to provoke cellular repair mechanisms.

          • Cisplatin is also capable of binding to adjacent guanine some the same DNA strand, thus producing intrastrand cross-linking and breakage.¹⁰

    • 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 

        • Human Copper Transporter (CTR1)¹⁴

          Attribution: Haas K Introduction to Ctr1:  https://www.youtube.com/watch?v=ufiEZy1so_Y (10/2016) PDB Coordinates:  Tsigelny IF Sarikov Y Greenberg JP Miller MA Kouznetsova VL Larson CA Howell SB An All-Atom  Model of the Structure of Human Copper Transporter 1 Cell Biochemistry and Biophysics 63(3) (2012):  223-234. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3590913/ Kathyrn Haas Youtube Channel:  https://www.youtube.com/channel/UC3hj87PikcaGy0t1-Rh0DOQ

        • 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.

          •  As such, this drug has an electron-deficient metal atom (platinum) which is attractive for electron-rich DNA nucleophiles..⁷ 

          • As noted earlier, organoplatinum antineoplastic drugs exhibit bifunctionality given that they can accept electrons from to DNA nucleophiles.

          • Cross-linking with interstrand is most likely between adjacent guanine residues (diguanosine dinucleotides, about 60% in frequency) or between adenine in guanine adjacent residues (about 27% in frequency).

            • Cross-linking between DNA strands (interstrand) occurs much less frequently than intrastrand cross-linking.⁷

      • Cisplatin aquation is more likely to occur intracellularly and in urine due to low chloride concentration.¹ 

        • By contrast, high concentrations of chloride tend to stabilize the drug, finding consistent with the observation that cisplatin-induced nephrotoxicity is prevented by chloride diuresis.

      • As noted earlier, formation of DNA-platinum adducts inhibit both transcription and replication.¹ 

        • 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.

          • Oxaliplatin adducts tend to be bulkier and resist repair.

          • Oxaliplatin is unique in that its cytotoxicity does not require an active mismatch repair system (MMR system).

            • "DNA mismatch repair protein, C-terminal domain"¹²

              By Jawahar Swaminathan and MSD staff at the European Bioinformatics Institute [Public domain], via Wikimedia Commons DNA mismatch repair protein PMS2 https://commons.wikimedia.org/wiki/File:PDB_1h7u_EBI.jpg https://en.wikipedia.org/wiki/DNA_mismatch_repair

          • Oxaliplatin is also less dependent on "High Mobility Group" (HMG) proteins required by other platinum analogues.^1,11 

          • Testicular cancer exhibit high concentrations of HMG proteins and shows substantial cisplatin sensitivity.^1,11  

        • Cancers that exhibit enhanced apototic pathways also exhibit increase susceptibility to cisplatin.

        • Cisplatin exhibits differing cell-cycle specificity dependent on cell type; for example, cross-linking effects appear most notable during the S phase.¹

    • Resistance to Platinum Analogue Antineoplastic Effects (Cisplatin and others)

      • A number of factors appear to contribute to resistance to the anti-neoplastic effects of platinum-based drugs.¹ 

        • Mechanisms that appear important in the development of platinum-based chemotherapy include:⁹

          • Decreased cellular accumulation of drug

          • Detoxification of the drug intracellularly

          • Platinum-DNA lesion repair

            • Increased DNA repair appears particularly important in tumors especially sensitive to the action to cisplatin. An example of this type the tumor is testicular nonseminomatous germ cell tumors that exhibit deficiencies in repairing DNA-platinum adducts. Repair of platinum-DNA adducts usually involves nucleotide excision repair and under some circumstance mismatch repair (MMR).⁹

          • Higher tolerance to damage induced by platinum-based drugs and

          • Activation of cellular defenses such as autophagy.⁹

            • Autophagy represents mechanisms that induce changes in a variety of systems, following detection by the cell DNA damage.⁹ 

              • These changes run counter to initiation of programmed cell death, thus allowing survival.

            • Approaches that reverse autophagy can result in increased sensitization of tumors to cytotoxic drugs.

        • Other factors including tumor microenvironment, effects due to other cells and metabolites likely represent other resistance pathways.⁹

    • Absorption, distribution, Metabolism Excretion:

      • Cisplatin is administered by IV infusion for treating metastatic testicular and ovarian cancer and advanced bladder cancer.⁷

        • Elimination is mainly renal, although about 10% of a dose is excreted in the bile.

        • Cisplatin is highly nephrotoxic and can induce renal tubular pathology with patients with pre-existing diseases especially vulnerable.⁷ 

          • To decrease the likelihood of renal toxicity, a chloride diuresis by infusion of 1-2 L of normal saline before beginning therapy is necessary.¹ 

          • Cisplatin than is itself diluted in a solution containing dextrose, mannitol, and saline, with resultant mixture administered over a 4-6 hour period.

          • Aluminum inactivates cisplatin requiring isolation of the drug from contact with aluminum-containing equipment.

      • Following IV administration cisplatin exhibits an initial plasma illumination half-life of about 30-60 min.

        • A second phase involving a decline in bound and unbound drug exhibits a half-life of the day or more.

        • Cisplatin is found in high concentrations in several organs including liver, intestine, kidney, ovaries, lung and testes.^1,10 

        • However, cisplatin does not enter the CNS easily.

      • Cisplatin undergoes nonenzymatic metabolism: the drug is in activated in the blood and in cells by sulfhydryl groups. Furthermore the drug binds, covalently, to glutathione and thiosulfate.¹⁰

    • Toxicity:⁹

      • Side effects associated with cisplatin administration at doses exceeding 50 mg/m2 include: ⁹

        • Nausea and vomiting

        • Ototoxicity

        • Nephrotoxicity

        • Neuropathy and

        • Myelosuppression.

      • Less common side effects are more numerous and consist of visual impairments, arrhythmias, seizures, glucose intolerance, pancreatitis, and acute ischemic vascular occurrences.

      • Since cisplatin exhibit substantial emetogenic effects, cisplatin-induced nausea and vomiting has resulted in an effort to determine the best medications to mitigate this effect.

        • Nausea and vomiting due to cisplatin are most effectively managed by combination of 5-HT₃ blockers along with a glucocorticoid.⁹

          • Other combinations are still used.

        • Antiemetic treatment may be required even four weeks following cisplatin.

      • Nephrotoxicity, as noted above, may be improved by hydration; however, nephrotoxicity may not be completely prevented by this intervention.

        • Glomerular and tubular damage due to cisplatin tends to be cumulative and following cisplatin treatment, glomerular filtration rate (GFR) is not reliably estimated by serum creatinine levels.

      • Ototoxicity is an important adverse effect of cisplatin administration and results from inner ear damage.⁹

        • Ototoxic effects in this setting is unfortunately both cumulative and irreversible.

          • Early manifestation presents as reduced high-frequency acuity.

          • Cisplatin should be discontinued, usually, if hearing acuity becomes diminished in the range associated with speech. In this circumstance, carboplatin may be substituted.

            • The influx copper transporter, CTR1, plays a role and cisplatin ototoxicity.¹⁴ 

              • In a mouse model, CTR1 was not only expressed but clearly localized at primary sites of cisplatin toxicity in the inner ear including:¹⁴ 

                • Outer hair cells

                • Inner hair cells

                • Stria vascularis

                • Spiral ganglia, and

                • Nerves surrounding the cochlea.¹⁴

              • If copper sulfate, CTR1 substrate, was present, cisplatin cytotoxicity and cisplatin uptake was decreased.¹⁴

                • In mice, intra-tympanic injection of copper sulfate before intraperitoneal cisplatin administration was sufficient to eliminate hearing loss in a click stimulus model.¹⁴

                  • Perhaps, cisplatin-induced ototoxicity may be modulated by the use of CTR1 inhibitors.

            • "Cisplatin-associated Hearing Loss in Children-The Past, Present and Future"¹³

              Freyer D Keck School of Medicine UCLA (Rare Disease Report) Cisplatin-associated Hearing Loss in Children-The Past, Present and Future. Published:  October 15, 2017 49th Congress of the International Society of Paedriatic Oncology (October 12-15, 2017) https://www.youtube.com/watch?v=98T3MLY6lrc

      • Peripheral neuropathy secondary to cisplatin also appears to be cumulative. However, this type of neuropathy is usually reversible but associated with slow recovery.⁹

    • Some Clinical Uses:

      • Metastatic testicular cancer is treated with cisplatin often in combination with other chemotherapy drugs, in patients previously having received surgery and/or radiation therapy.¹⁰

        • More specifically, cisplatin may be combined with bleomycin, etoposide, or with vinblastine and ifosfamide with administration associated with cure in about 90% of individuals with testicular cancer.¹

      • Metastatic ovarian cancer utilizes cisplatin often in combination with other drugs, for patients previously having received surgery and/or radiation therapy.¹⁰ 

        • Administration of cisplatin or carboplatin in combination with paclitaxel results in complete response for most patients with ovarian carcinoma.¹

        • Treatment with cisplatin as monotherapy is appropriate for tumors unresponsive to standard chemotherapy for those patients who have not previously been prescribed cisplatin.

          • Recurrent Ovarian Cancer: Case Study¹⁶

            Westin S Recurrent Ovarian Cancer:  Selecting Second-Line Therapy.  Targeted Oncology, April 27, 2018 https://www.youtube.com/watch?v=9bla_50S9lM https://www.targetedonc.com/

      • Monotherapy with cisplatin for treating advanced bladder cancer (transitional cell disease) is appropriate for patients considered no longer appropriate candidates for local therapy which may include surgery and/or radiation treatment.¹⁰

      • Cisplatin induces responses in bladder cancer, head and neck cancer, cervical and endometrial cancer.¹

      • Furthermore, cisplatin appears useful in treating lung carcinoma, rectal and anal carcinomas and childhood neoplasms.

        • Local control of advanced cancers such as lung, head and neck, and esophageal, may be improved when radiation is given to tumor cells sensitized to radiation by cisplatin.¹