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New Chemotherapy Drugs

Drugs requiring dose modification in the setting of hepatic dysfunction, and I’ve listed here the drugs that you really have to think about. So anthracyclines, doxorubicin, daunomycin, the taxines - Taxol, Taxotere; the vinca alkaloids, vincristine, vinblastine, vinorelbine, m-AMSA, thiotepa, and even though CPT-11 is not yet completely established, I think most people would say that in the setting of liver dysfunction you really have to be very careful.

Drugs requiring dose modification in the setting of renal dysfunction, and usually the suggested dose modification is in proportion to the creatinine clearance. The antimetabolites, the anti-folate analogues, methotrexates, and as well 2-chloro deoxyadenosine, fludarabine, 6-mercaptopurine, the platinum analogues; cisplatin, carboplatin, Cytoxan, ifosfamide, bleomycin, Hydrea, VP-16, streptozocin, and topotecan. So the one thing I would just bring to your attention, as you can see, most classes of drugs are very similar. So you’ve got the anti-folates and the purine analogues.

So lets get into the drugs themselves. So this first hour we are going to touch on the anti-metabolites; methotrexate. As you can see it’s a fairly old drug. The most widely used anti-folate in cancer chemotherapy. Has a wide spectrum of action; leukemia, lymphoma, breast cancer, head and neck cancer, osteogenic sarcoma, colon cancer, bladder cancer, choriocarcinoma. Just to remind you that it looks just like the natural reduced folate, tetrahydrofolates, that’s made up of three different components. A pteridine ring, a peramino-benzoic acid moiety and glutamyl residues. It is these glutamyl residues that get tacked on here to methotrexate that allow the drug to stay within the cell.

Inhibition of de novo purine and thymidylate biosynthesis by both methotrexate and dihydrofolate polyglutamates, an inhibition of DNA synthesis and function by missing incorporation of DUTP into DNA. I think for a long time it’s always been felt that number one was the main mechanism. I think it’s now appreciated that probably it’s a combination.

In terms of mechanisms of resistance, probably the first two that … actually three, because they will be on the next slide, are probably the most important in terms of the clinical setting. Decrease in the karyo-mediated membrane transport. So methotrexate and many of the antifolate analogs require specific transport into the cell, and it can be transported mainly by the reduced folate carrier, RFC, and also the folate receptor protein, FRP. Since dihydrofolate reductase is a target it’s not surprising that if you have increases in the target, dihydrofolate reductase, either through amplification - I should have included transcription - as well as translational mechanisms - that means, you need to have more drug to do its thing. Alteration in the binding affinity of the dihydrofolate reductase for methotrexate; this is probably a minor mechanism, in terms of the clinical setting. This next one, number four, probably should go up to number three; decrease in formation of cytotoxic methotrexate polyglutamates. So again, remember, we talked that methotrexate needs to be polyglutamated. It needs to have up to five to seven additional glutamyl residues in order to be cytotoxic. So how do you get less formation of the cytotoxic polyglutamates? You can have either decreased levels of the enzyme that tacks onto the glutamyl residues, that’s FPGS, folo-polyglutamate synthase.

In terms of clinical pharmacology, as some of you may know, oral methotrexate is fairly well absorbed at doses less than 25-30 mg per meter squared. But once you get to higher doses, the bioavailability is quite erratic. Key issue is major route of elimination is via renal excretion and this process can be inhibited by aspirin, penicillin, probenecid, non-steroidals, cephalosporin. And patients who have impaired renal function need to have their dose of methotrexate reduced in proportion to the creatinine clearance. So that’s important. A very small percentage, less than 10%, is excreted via biliary process but it is interesting that in the setting of renal dysfunction this number may actually go up, but as yet there are really no dose modifications required in the

Toxicity; a key point for the toxicity for all the anti-metabolites are that the host toxic effects are dose, schedule and route dependent. Myelosuppression is the usual dose limiting toxicity. One can also see GI in the form of mucositis and/or diarrhea. It usually appears 3-7 days after methotrexate therapy and generally tends to precede the onset of myelosuppression. Nephrotoxicity results from the intratubular precipitation of methotrexate and its metabolites. Methotrexate may also exert a direct toxic effect on the kidney tubules. And to try to reduce the

Hepatotoxicity; you can see both acute hepatotoxicity and that’s usually in the setting of high dose methotrexate. Usually resolves. Chronic hepatotoxicity; we typically don’t see that in oncology. It’s the rheumatologists who usually see it when they are treating patients with psoriasis or rheumatoid arthritis. It’s clear now that if you give weekly pulsed doses of methotrexate, as opposed to oral continuous methotrexate, you can actually decrease the incidence of fibrosis and/or even cirrhosis resulting from methotrexate. You can also get

Neurotoxicity; there are mainly two distinct syndromes observed with high dose methotrexate therapy. One is an acute encephalopathy which occurs in the first week of methotrexate therapy and usually resolves within two or three days. Consists of acute transient cerebral dysfunction with paresis, aphasia, behavioral abnormalities, and/or seizures. There can also be a chronic encephalopathy which can look for all the world just like dementia. It usually develops within the second or third month following therapy and consists of a dementia-like syndrome and also can present with motor paralysis. Neurotoxicity can also be observed when you use the intrathecal form of methotrexate therapy, so this is again the prophylactic treatment in patients with high grade lymphomas and also direct treatment of a meningeal carcinomatosis, meningeal leukemia and/or lymphoma. So you can get an acute chemical arachnoiditis which occurs immediately after intrathecal therapy, presenting with headache, nuchal rigidity, vomiting, fever and

So that’s methotrexate. Let’s move on to the fluor-primadine 5-fluorouracil. Again, an oldy but still used in the clinic. Synthesized in the late 1950’s, 1957 for those of you interested in history. Has widespread clinical activity, particularly GI malignancies, colorectal cancer, but also breast, head and neck, pancreas, ovarian cancer. I have a copy showing the most active 5-FU drugs that are currently being used; 5-fluorouracil is the base, flurodeoxyuridine is F-udr. This is the form of the drug that is used for intrahepatic arterial installation, 2-R4 is part of Uft and 5-prime deoxyflurouridine is part of capecitabine, Xeloda. This just shows you to remind you that 5-fluorouracil by itself is inactive, and that’s also an important thing to remember. All the

Now a pathway that we don’t think about very much is the catabolic or breakdown pathway, 5-fluorouracil, but this makes up about 80-85% of what happens to the drug once we give it to patients. The drug that catalyzes the rate-limiting step in this process is called dihydropryrimidine dehydrogenase, also known as DPD. And this .. you may see this on the exam. It’s actually quite interesting. So patients who have a deficiency in this enzyme develop what’s called a pharmacogenetic syndrome and they manifest as intense, grade III or grade IV toxicity in the form of myelosuppression, GI toxicity, mucositis, diarrhea, and/or neurotoxicity. So the usually rule of thumb, the usual feeling … Bob Diazu of University of Alabama had initially described this in the early 80’s and Bob’s initial discussions had said that you kind of had to have all three; myelosuppression, GI, neurotoxicity, but actually about three or four years ago we

In terms of mechanism of action, again what we’ve been brought up with since medical school is that inhibition of the target enzyme, thymidylic enzyme by the 5-FU metabolite SU-MT kind of is the main mechanism of action. But there may be other mechanisms, including incorporation of 5-FU nucleotides, FUTP in to RNA resulting in alterations in RNA processing and RNA translation, incorporation of FU nucleotide FTUTP into DNA resulting in inhibition of DNA synthesis and function, and also mis-incorporation of DUTP into DNA resulting in inhibition of

In terms of resistance; increased expression of the target enzyme through gene amplification, transcription, translation. Okay, this is probably the most commonly described mechanism of resistance both in the laboratory and in the clinical setting. Decreased levels of the reduced folate, 5-10 methylene tetrahydrofolate, and this is the reason, or this was the rationale, for giving leucovorin. So leucovorin is the reduced folate 5-formotetrahydrofolate. So you are repleting the pools of reduced folate that in about 20-30% of patients are relatively deficient. So that probably explains why, at least in the beginning, we were seeing about 25-30% response rate when we combined 5-fluorouracil with leucovorin. You are going to have decreased

Drug interactions to just think about; methotrexate and 5-fluorouracil was actually developed at Yale by Ed Cadmon and Joe Bertino in the 1970’s. They always like to ask this question because it’s been well documented. So you have to give methotrexate before 5-fluorouracil, optimal timing is 24 hours, both in the laboratory and also now confirmed in the clinic. Methotrexate increases the formation of 5-FU nucleotide metabolites when given prior to 5-fluorouracil. Again, timing is critical with a 24 hour time interval. So if you give it at the same time or you give methotrexate afterwards it doesn’t work. All of you should know 5-FU leucovorin - this is also a very common Board question - leucovorin is 5 formiminotetrahydrafolate, provides the requisite folates necessary to enhance the inhibition of thymidylate synthase. So to inhibit thymidylate synthase you need a ternary complex. So that’s 5-FU, metabolite FDUMP, the

Cardiac; syndrome of chest pain, EKG changes, serum enzyme elevations, and you do need to pay close attention to patients who have a previous history of heart disease and in particular those who have active ischemic heart disease. Ocular toxicity is kind of like a mucositis but instead of the GI tract you are affecting the eyes. So it can present as blepharitis, tear duct stenosis and acute and chronic conjunctivitis. Finally, with hepatic artery infusional therapy you can have cholestatic jaundice with biliary sclerosis and also gastritis and