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New Chemotherapy Drugs

So for the second half we are going to go to all the other main classes of drugs. So we’ll hit platinum agents, taxines, anthracyclines, highlight the alkylating agents, Vinca alkaloids, VP-16 as a member of the etoposidal toxins, just a couple of anti-tumor antibiotics and then end with the camptothecin.

Okay, so the platinum analogs; we’ll hit cisplatin, carboplatin, and also oxaliplatin now that that’s becoming more widely used. Cisplatin is the first metal compound to have clinical anti-tumor activity. We won’t go into it but for those of you who are interested, this actually was discovered serendipitously by Dr. Rosenberg in the late 1960’s.

Mechanism of resistance; cisplatin does get transported into the cell. It’s not really clear exactly what the transport mechanism is, but it’s now been described that you can have reduced accumulation of cisplatin, alterations in cellular transport. A key mechanism of resistance; increased inactivation by thiol-containing proteins such as glutathione and glutathione-related enzymes. So akin to this, can you think of a compound that is now used in the clinic.

Clinical pharmacology; key point, rapidly equated whereby the choroid atoms - and there are two of them on cisplatin - are replaced by water molecule, high concentrations of chloride in the plasma maintain the cisplatin in the uncharged form. In the cytoplasm, however, the concentration of chloride is low so it favors the replacement of the chloride atoms by OH negative groups. That’s the reactive species that targets DNA.

The key drug interactions to keep in mind; cisplatin/Taxol. Cisplatin when given before Taxol can decrease the systemic clearance of Taxol, resulting in higher plasma levels. This was shown by Rostonhower and his group at Johns Hopkins a number of years ago. And when cisplatin was given before Taxol it was associated with increased toxicity, myelosuppression, a form of neutropenia.

Toxicity. Renal toxicity is dose limiting. The cisplatin adducts can attack the loop of Henley, the ascending and the collecting ducts. Renal toxicity can be manifested in the form of hypomagnesemia and hypocalcemia. Recall that they typically go hand-in-hand. Before the use of Zofran and Kytril, back when I was a fellow, nausea and vomiting actually in some cases was dose limiting. But that really has become a much less significant problem, although every once in awhile you’ll have a patient who even can respond to Zofran or Kytril.

Moving on to carboplatin; the second generation platinum compound. The mechanism of action is identical although it seems to be about four-fold less potent than cisplatin. Mechanisms of resistance is identical to cisplatin. Clinical pharmacology; primary route of excretion is renal. It’s even more renal than cisplatin. So dose modification is absolutely required in the setting of renal dysfunction.

Toxicity; myelosuppression usually is dose limiting. In some cases it’s thrombocytopenia, in some patients it’s neutropenia, nausea, vomiting. Renal toxicity is a bit unusual, only at the higher doses and in patients with renal dysfunction. Neurotoxicity really at more transplant-like doses. One issue just to keep in the back of your mind, not only for the Boards but also just day-to-day, in your clinical practice are carboplatin and cisplatin exactly the same in terms of how they work, and can you use them interchangeably in clinical regimens?

Oxaliplatin; a third generation compound. Good activity in colorectal cancer as a single agent. Again, most of this comes from Europe and in France where it has a 10-18% single agent response rate, in combination with 5-FU leucovorin, response rates go up into the 30-40% range. Now oxaliplatin has come here across the ocean to the United States. The mechanism of action is identical to that of cis and carboplatin.

Let’s move on to the taxines, Taxol. Again, it actually is a golden oldy in terms of when it was first isolated, back in the 1960’s from the bark of the Pacific yew tree, Taxus brevifolia. You don’t really need to know the structure and I think I even took out the structure this year. It’s very active clinically and has broad spectrum activity against breast, non-small cell lung cancer, small cell lung cancer, head and neck cancer, ovarian cancer, bladder cancer, testicular cancer, to name just a few. How does it work? The key thing to remember is that it attacks the microtubules but it acts completely different than the Vinca alkaloids. So Taxol, Taxotere act the same. High affinity binding of the drug to microtubules.

So Taxol, mechanism of resistance, the key ones are alterations in tubulin with an impaired ability to polymerize tubulin dimers into microtubules. This is probably numero uno. And the second mechanism is the MDR, multi-drug resistant phenotype, with increased expression of P-glycoprotein, the P-170 glycoprotein. What that does is that enhances efflux of drugs out of the cell so there is cross resistance to the Vinca alkaloids, the anthracyclines, cultracine, VP-16.

Toxicity: neutropenia is usually dose limiting, not cumulative and recent evidence - this is probably a number of years ago, five or six years ago - from the NCI of Canada show that the shorter drug infusions, three hour, may actually be associated with a lower level of neutropenia and myelosuppression when compared to the 24-hour infusion. It’s clear that if you give Taxol 72-hour or 96-hour infusion the myelosuppression.

Clinical pharmacology: identical. The P-450 system in the liver plays a major role in the metabolism of Taxotere so dose reduction of the drug needs to be considered in patients with moderate or severe hepatic dysfunction. So just like Taxol. Renal clearance is insignificant.

Toxicity: the neutropenia seems to be dose limiting just like Taxol. Also, you can get major and minor hypersensitivity reactions occurring in about a quarter of all patients receiving drug without pre-medication. Interestingly, Taxotere is formulated in a different vehicle. It’s actually formulated in polysorbate 80, so it is different than the Cremophor-EL.

Let’s move on to anthracyclines; doxorubicin, daunomycin, daunorubicin. We’ll just stick to mostly doxorubicin, Adriamycin. It has broad spectrum activity in solid tumors, breast, ovarian, thyroid, non-small cell lung, small cell lung, soft tissue sarcomas, and also hematologic malignancies; Hodgkin’s and non-Hodgkin’s lymphoma. How does it work? Things have changed quite a bit. Back when I was a medical student the prevailing was that it was direct intercalation of the drug into DNA resulting in inhibition of DNA synthesis and function.

Adriamycin, dose limiting toxicity: myelosuppression. In some patients, GI toxicity in the form of mucositis. Alopecia usually universal. Cardiotoxicity; really two forms. There can be an acute/ sub-acute form and there can be a chronic form. The acute form is completely unrelated to the dose. It occurs within the first 24, 48, 72 hours of drug administration and it’s kind of like an acute pump failure, acute LV dysfunction. Patients can present with pericardial effusions, pleural effusions, actually what’s called the myopericarditis syndrome. Usually reversible.

Just to touch on a couple of Adriamycin analogs. Mitoxantrone has actually received renewed interest. It does have activity against breast cancer but I guess where the interest has been renewed is in its activity against prostate cancer in combination with prednisone and also in the treatment of low grade indolent lymphomas with the F&D regimen.