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mdr-defying compound in phase i trial tularik's anticancer
drug stops microtubule- driven cell division, halts tumors in xenografted
mice
BioWorld via NewsEdge Corporation : A cancer patient on multidrug chemotherapy has more to lose than his hair and his breakfast. Time is against him.
"In this commonly encountered clinical situation," explained physician Andrew Perlman, "tumors initially respond to the existing chemotherapeutic agents. Patients undergo a number of cycles of therapy, which seem to control the cancer. But then his or her tumors become less and less responsive to the treatment, and ultimately the patient needs other forms of therapy - or succumbs to the disease."
Perlman is vice president of medical research and corporate development at Tularik Inc., of South San Francisco. His company is now testing, in mice and people, such another form of cancer therapy. It's described in the current issue of the Proceedings of the National Academy of Sciences, dated May 11, 1999. The paper bears the title: "Selective, covalent modification of beta- tubulin residue Cys-239 by T138067, an antitumor agent with in vivo efficacy against multidrug-resistant tumors."
Except in name, tumor multidrug resistance (MDR) differs radically from the explosive inroads by infectious pathogens, such as tuberculosis and Staphylococcus aureus, against the arsenal of antibiotics that used to slay such bacteria.
"It's not the case," Perlman pointed out, "that from widespread use of these anticancer agents, more and more tumors are coming up, right from the beginning, resistant to multiple drugs. Some are, some aren't. But it's not as if we're generating new tumor types that have resistant phenotypes, such as seen in the bacterial diseases."
Perlman continued: "Neoplastic cells, both in tissue culture and in actual tumors in patients, are very adept at becoming resistant to a variety of chemotherapeutic agents. One of the common resistance mechanisms that cancer cells use is pumping the foreign cytotoxic agent out of their cytoplasm. The notion that we have here at Tularik is that our T138067 compound may overcome the cancer cell's ability to pump that chemotherapeutic out, before it has a chance to get in its antitumor licks.
"We have reason to believe," Perlman told BioWorld Today, "that our compound, by virtue of its mechanism of action, cannot be pumped out of the cells. It is also likely not a good substrate for many of the pumps, which are glycoproteins expressed by the MDR genes."
Their compound's mode of action goes back to the nanometer-sized cylindrical microtubules that support the cell's cytoskeletal physical structure and rigidity. More to the point, microtubules control a cell's division into two daughter cells - the process of mitosis.
Molecular biologist Holger Beckmann, senior author of the paper, explained: "Basically, microtubules are composed of tubulin heterodimers - that is, two unpaired molecules, alpha and beta. Beta- tubulin exists in five subclasses. Although these proteins are very homologous, they differ at one particular amino acid position, number 239. In three of the five isotypes, 239 is a cysteine; in the others, a serine.
"And that's where our compound comes into the game," Beckmann told BioWorld Today. "It binds only to a cysteine, 239, and as a consequence of all of this you get depolymerization - breakdown - of the tumor cell's microtubular network."
He made the added point that, "In this respect, our T138067 compound works just the opposite of Taxol [a front-line agent against breast and ovarian cancer], which stabilizes the microtubule network. Our compound disrupts it, preventing the growth of the microtubule fibers. This disruption somehow triggers the cell-cycle arrest in mitosis. Subsequently, by mechanisms we really don't know yet, the compound induces apoptosis of the tumor cell.
"Whereas Taxol, on the other hand," Beckmann recounted, "binds to the formed microtubules. So that's where the two compounds distinguish each other by their mode of action."
He added, "Microtubules are identified as something like strings that are pulling the chromosomes apart during cell division, which guarantees that each of the daughter cells gets the same set of chromosomes."
Perlman observed: "What is known from the Taxol experience, as well as the vinca alkaloids in clinical use, is that microtubules are the highways along which the chromosomes travel to accomplish cell division. If you foul up the highway, either by breaking them into pieces, as the vinca does, or stabilizing them in a certain way so they can't continue their renewal process, cell division can't occur. The chromosomes can't migrate along those highways any more. Ergo, tumor cell growth stops."
Tularik pitted its T138067 antitumor agent against Taxol and vinblastine in immune-deficient nude mice. First, they grafted human leukemia cells into separate groups of animals, each of which then received weekly chemotherapy with one of the three agents. In initial dosing, all three had comparable efficacy. But against a subline of leukemia cells resistant to Taxol and vinblastine, T138067 turned in the same antitumor performance as with the non- resistant neoplasms, while the two other drugs showed a 50 percent decrease in efficacy.
Phase I Data Expected By Year's End
In March of last year, Tularik began a Phase I dosage-escalation study of its compound at the Memorial Sloan-Kettering Cancer Center in New York. "The inclusion criteria," Perlman elaborated, "are for patients with advanced refractory solid tumors. That's a typical Phase I study design, with safety and dosage as primary endpoints." As an unanticipated clinical datum, he added, "it is perfectly possible that some patients may have a favorable response to therapy, but that is not one of the primary objectives of the study."
"All patients are not yet enrolled," Perlman explained, "because this is a dose-escalation study, and one of our goals is to define the MTD - maximum tolerated dose - which escalates until you've reached that level. We're not there yet. So we have not enrolled the totality of patients at this time." N
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