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New Treatments for Chemoprotection

The chemotherapy drugs and their chemoprotective agents; anticancer agent, methotrexate. The main protective agent that weíve used has been leucovorin. So leucovorin is reduced folate 5- formyl tetrahydrofolate. But also some people have used thymidine and Iíll just show you why that can work in some instances. 5-fluorouracil, thereís really no standard way to protect or rescue against the host toxic effects of 5-fluorouracil but two ways that at least one can think about are thymidine and/or uridine. Cisplatin, as you all know, amifostine, thiol or WR-2721 has now been approved. Adriamycin, doxorubicin, dexrazoxane, ICRF-187 and ifosfamide and Cytoxan, high dose Cytoxan in the setting of stem cell transplant, mesna. I didnít have any slides or handouts for mesna so really very quickly I will just say is - we already talked about it - mesna is known as sodium tumor captoethane sulfonate. So it is a thiol compound and the key issue is that it is restricted to the urinary system. So itís rapidly cleared by the kidneys and what it does is; free thiol binds presumably to the acrolein metabolite of ifosfamide and Cytoxan.

So amifostine, a thiol, WR-2721, is an organic thiol phosphate originally developed by the Walter Reed Army Institute of Research in their hope of identifying agents that could be used to protect troops exposed to nuclear radiation and basically biological warfare. In all they screen about 4400 different compounds and came up with this guy. In terms of mechanism of action and key points to remember, it is inactive in its parent form and requires activation by the enzyme alkaline phosphatase, which is located on the plasma membrane surface of endothelial cells lining the blood vessels, and also on the surface of proximal renal tubular cells.

In terms of clinical activity, itís been approved for use to protect against nephrotoxicity from cisplatin-based therapy for the treatment of advanced ovarian cancer, and as well non-small cell lung cancer. Whatís nice is it protects against the renal toxicity but thus far does not appear to compromise the anti-tumor activity and response rate of cisplatin-based regimens. So itís FDA approved for this. It also has recently been FDA approved to prevent radiation-induced xerostomia. So if you will, amifostine has been viewed as kind of a broad spectrum

Key points of clinical pharmacology: itís rapidly cleared from the plasma. Has a very rapid distribution half-life, a very short elimination half-life and less than 10% of the drug remains in the plasma six minutes after drug administration. So for this reason you actually have to give this drug to a 15 minute infusion and you have to give it 30 minutes before cisplatin chemotherapy. Now a number of investigators have actually tried to give the drug either at the same time or 30 minutes after cisplatin, and under those cases there is absolutely no protection from renal toxicity. So you have to give it before, you have to give it for 15 minute infusion. But the

Okay, so moving on to the next chemoprotective agent is dexrazoxane, also known as ICRF-187, also known as Zinecard. So by itself, in its parent form, it is inactive and requires hydrolysis intracellularly by either enzymatic or non-enzymatic mechanisms to yield an EDTA analog. This is the key point. This analog is a chelator of iron and it strips iron from the Adriamycin iron complex, thereby preventing free radical formation. So because this agent is a chelator of iron and prevents formation of free radicals and protects against cardiac toxicity, I think this is another piece of evidence to say that the cardiac toxicity is really due to free radical formation. There doesnít appear to be any kind of pharmacokinetic interaction between this drug and

Also there is significant cardiac protection in patients older than 65 years, and in those patients who have ejection fractions that may be kind of low-normal.

Toxicity: myelosuppression is dose related but appears to be reversible. Number two I just included to be complete, there is some suggestion from animal models that actually there is the potential risk of secondary malignancies, in particular AML, with prolonged use. This actually may be related - just like with VP-16 - to effects on Topo II and chromosome 11 and 22. Important point: cardiac protection has been observed for other tumor types in pediatric patients with sarcoma and also in patients with small-cell lung cancer. As well it has been observed.