If your foot "goes to sleep," it usually wakes up again.Not so with ovarian or breast cancer patients receiving high-dose Taxolchemotherapy. Over half of them suffer severe, often irreversible, side-effects in the form of paresthesia (tingling; numbness) and dysesthesia(burning, shooting, stabbing pains).These neurosensory reactions to the anti-cancer drug can be so severethat the attending oncologist must discontinue the potentially life-saving Taxol treatment.Yesterday at the Experimental Biology Conference in Anaheim, Calif.,Patricia Contreras, associate director of experimental pharmacology atCephalon Inc., reported that recombinant human insulin-like growthfactor (rhIGF-1) is a possible remedy for the neuropathic side effects ofthe antitumor agent.Mice given Taxol developed a sensory neuropathy, as shown by theirresponse times in the standard tail-flick and hot-plate tests."Administration of rhIGF-1," Contreras' poster stated, "completelyprevented the Taxol effects," in a dose-dependent manner.In clinical use of Taxol, Cephalon's vice president of research, JeffVaught, told BioWorld, "at the recommended maximum dosage of 150milligrams per square meter of body surface, we begin to see sideeffects." He added, "Due to the newness of Taxol, clinical studies ofincrements above this dose have not been done, obviously, becauseoncologists adjust dosage to stay out of the neuropathy region."Instructions to physicians for use of Taxol in treating ovarian canceradvise that at the recommended dose, 52 percent of patients get sensoryneuropathies.At 250 mg/sq. m., according to a Phase II study in breast cancer, 96percent of women suffered the side effects, and declined in a dose-related manner.The up-side of this downer was presented two weeks ago at the 85thAnnual Meeting of the American Association for Cancer Research, inSan Francisco. David Stong of Cephalon's drug metabolism groupreported, in a poster, that rhIGF-1 actually enhanced the antineoplasticeffects of cisplatin chemotherapy against human lung and breasttumors implanted in mice. Although the growth factor did not have thesame tumor-reducing result with vincristine, it did not affect the growthof malignancies treated with that drug.Unlike Taxol, which targets sensory neurons, vincristine's side-effectsattack motor neurons. Cephalon's rhIGF-1, said Vaught, can not onlyreverse neuropathy but actually enhance tumor kills of thechemotherapeutic. Last year, he said, the company, based in WestChester, Pa., licensed a patent held by the Wakunaga company ofOsaka, Japan, covering the utility of a growth factor to enhance tumorkill by chemotherapy.Meanwhile, Cephalon's rhIGF-1, trademarked Myotrophin, is 16months into a Phase III clinical trial for treatment of amyotrophiclateral sclerosis (ALS _ Lou Gehrig's disease). It has enrolled 230patients at eight centers throughout the U.S., and will be completed byyear's end. Last October, similar trials began at eight ALS clinics in sixEuropean countries (See BioWorld Today, Oct. 6, 1993, p. 3), with 70patients acquired to date."All that we know of rhIGF-1's mode of action," said Vaught, "is thatit supports neuronal function. Its role in the overall survival of neuronsis still being unraveled."Neurologist Stuart Apfel of Albert Einstein College of Medicine in TheBronx, N.Y., works primarily with neurotrophic factors and peripheralnerve diseases. Commenting on Cephalon's rhIGF-1, he toldBioWorld, "I'm impressed by its mitigating effects on neuropathy."Apfel emphasized that "because more and more agents are beingdeveloped to fight cancer, or infectious disease _ even AIDS withAZT and ddi _ neurotoxicity is the major dose-limiting side effect."He added, "The approach that Cephalon is taking, which is somewhatpatterned after the one that we had done earlier, is a promising start,but primarily for the purpose of leading to clinical trials which I knowthat Cephalon itself is going to do."
-- David N. Leff Science Editor
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