POISON THE PUMP OR PILE ON MORE PUMPS? TWO-WAYCLINICAL TESTING JUST BEGUN
By David N. Leff, Science Editorand Ray Potter Special To BioWorld Today
Oncologists swear by taxol as chemotherapy for ovarian cancer. Butthey also swear at the drug _ for two opposing reasons:
* Taxol, the most potent ovarian tumor-cell killer yet discovered (inthe bark of yew trees), is also highly toxic to healthy cells, whichlimits its dose level, hence its efficacy.
* Many ovarian tumor cells quickly wise up to the taxol treatment,and develop multidrug resistance to pump the drug out, before it hasa chance to get in its therapeutic licks.
Two contrarian strategies to disarm both of these tumor-killer killersbegan Phase I clinical trials last week.
On Friday, hematologist/oncologist Albert Deisseroth of M.D.Anderson Cancer Center in Houston told the Third InternationalConference on Gene Therapy in Cancer, in San Diego, of his gene-therapy approach to add more pumps.
On Tuesday, Vertex Pharmaceuticals Inc., of Cambridge, Mass., saidthat it was starting clinical trials to test its anti-multidrug resistancechemical compound, VX-710 in ovarian cancer patients receivingtherapy with taxol.
Vertex president and chief operating officer, Joshua Boger, toldBioWorld Today that his dosage, pharmacokinetics and tolerabilitystudy of VX-110 will enroll up to 45 ovarian-cancer patients "at amajor U.S. cancer treatment center, with a great deal of experience inexperimental treatments."
It will take "most of next year," Bogor said, to complete this initialtrial of VX-710, because it will be administered to women getting upto six courses of taxol, at three- to four-week intervals.
Early in January, Boger added, a parallel Phase I clinical trial of VX-710 will pit the anti-multidrug resistance molecule against the anti-cancer drug, doxorubicin (Adriamycin) in subjects with other solidtumors. "These preliminary studies," he observed, "are not set up tomake statements about efficacy, but obviously, we'll be watchingthat, and gathering information anecdotally about response rates."
VX-710, he said, is a small, synthetic, proprietary molecule in the500-molecular-weight range. A drug-resistant tumor cell encodes themultidrug resistance gene, which expresses a 170-kilodalton protein,g-glycoprotein by name, that pumps out the taxol as fast as it comesin. The Vertex molecule, Boger explained, "binds to and blocks thisp-gp protein pump. By doing that, it prevents such cells fromprotecting themselves against cancer chemotherapy."
Vertex immunologist Matthew Harding reported on the preclinicalprofile of VX-710 in early September to the First InternationalConference on Reversal of Multidrug Resistance in Cancer, in St.Galen, Switzerland. Its in vitro potency, he said, checked out in apanel of drug-resistant cell lines, including leukemia, myeloma,melanoma, bronchogenic adenocarcinoma and breast cancer. Thecompound restored the toxicity of doxorubicin, vincristine,vinblastine, etoposide and taxol.
"Collectively," Harding stated, "the in vitro data indicate that themultidrug resistance inhibitor potency of VX-710 is similar to CsA(cyclosporin A), and fourfold greater than verapamil."
Boger observed, "As the conference's moniker indicates," this is afield that's come into its own."
He continued, "Sandoz is a leader in the field, because theydiscovered, by accident, that cyclosporin A, an immunosupressor,had another pharmaceutical action _ blocking that multidrugresistance pump.
"Another company that has recently upped the ante," he said, "isBASF's Knoll Pharmaceuticals. They have verapamil, a blood-pressure-lowering drug, in multidrug resistance clinical trials.They've also recently licensed in a compound by Japan's Mitsui,MS209, and have it in Phase I clinical trials. And Glaxo has a seriouspreclinical candidate."
Vertex, Boger said, is developing VX-710 entirely on its own "rightnow, but as always, we are in discussion with various interestedparties."
He cleared up one common ambiguity: "Tumor drug resistanceemploys an entirely different mechanism from resistance bypathogens to antibiotics. "You're talking about resistance with a lotof different organisms," he explained. It's not as clean a problem ascancer multidrug resistance. But Vertex is certainly interested inantibiotic resistance too."
Having determined the pharmacokinetics of VX-710 in rats anddogs, Boger concluded, "Now our primate studies have begun _ inpeople."
Making Healthy Cells Taxol-Resistant
M.D. Anderson's Deisseroth reminded his audience at the San Diegosession on hematopoietic progenitor cells that "all too often, therelatively non-selective toxic effect of chemotherapy and irradiationimposes limits on the doses of chemotherapy which can be safelyused."
He just launched a gene-therapy program to protect the mostsensitive tissue of the body, the blood-forming cells, from theseunbearable toxic effects.
In Deisseroth's approach, a retroviral vector transfers the multidrugresistance cDNA that encodes p-glycoprotein, to modify bone-marrow cells taken from the patient.
Thus made resistant to taxol, these hematopoietic cells aretransplanted back into the ovarian-(trial begun) or breast-cancer (trialimminent) patient, who then receives taxol chemotherapy.
Now able to resist the tumor killer, those healthy cells can toleratemuch larger dosage levels of the anti-cancer drug, sufficient tooverwhelm the tumor's multidrug resistance-driven efforts to pumpout the taxol, and effectively treat the malignancy.
Robert Sobol, co-director of the San Diego conference, and amember of the San Diego Regional Cancer Center which sponsoredit, told BioWorld Today: "If the Vertex drug inhibits that multidrugresistance pump, I think the two approaches are complementary.They come at it from different angles." He added, "Vertex'sapproach is to poison the pump _ make the tumor cells moresensitive to taxol, by inhibiting multidrug resistance.
"Deisseroth adds more pumps in normal cells, trying to make thesehealthy tissues of the body more resistant to taxol, so you can givehigher doses. You really end up almost in the same place witheither." n
(c) 1997 American Health Consultants. All rights reserved.