All the ways of treating cancer _ surgery, radiation,chemotherapy, immunotherapy _ have one aim: Kill thetumor cells. But aren't there ways to rehabilitate tumorcells instead of cutting, burning or poisoning them todeath?
One way that clinical oncologists are trying involvestaking a leaf from a natural compound, retinoic acid,currently prescribed to cure acne and widely used withoutprescription as an anti-wrinkle cream. Retinoic acid is anaturally occurring derivative of vitamin A, a fat-solublevitamin found mainly in milk, fish and liver oils, andsome vegetables. Many mammalian cells have receptorsspecific for retinoids, which seem to play a vital role incell differentiation and growth.
Reasoning that retinoic acid might induce potentiallymalignant embryonic stem cells to grow up anddifferentiate into mature white blood cells that don'tproliferate out of control, clinicians have administeredretinoic acid to cancer patients, with both good and badresults. The good news came several years ago fromChina, recalls Kenneth Cohen, vice-president of businessaffairs at Houston-based Argus Pharmaceuticals Inc.
Out Of China: Unbelievable Remissions
"In China," Cohen told BioWorld Today, all-trans-retinoic acid (ATRA) was administered orally topromyelocytic leukemia and Kaposi's sarcoma patients inmore-or-less properly done clinical trials, with strikinglygood results. Nobody believed them at first," he added,"because they were published in China."
Since then, numerous trials of oral ATRA in the U.S. andEurope have reported complete remissions in 90 percentpatients with promyelocytic leukemia (PML). The badnews soon followed: These apparent cures lasted only afew months, before the patients relapsed. Then a newround of ATRA therapy produced scant or no benefit.
Those presumably redeemed tumor cells had violatedtheir parole and killed again. They seemed to developresistance to nature's retinoid remedy, as they do sofrequently against conventional anti-cancerpharmaceuticals. Yet, when cancer cells taken frompatients who had relapsed after oral ATRA treatment,were exposed to the drug, it continued to inducedifferentiation.
The researchers now believe that, in a different patternfrom ordinary drug resistance, the oral route encouragesthe liver to remove the compound from the bloodstream.
Usually, drug discoverers strive to create orally ingestibleversions of injectable compounds, to make self-treatmentsimpler for patients. Conversely, researchers at M.D.Anderson Cancer Center, in Houston, suspected that theoral ATRA began losing its potency precisely because itwas swallowed instead of injected.
However, ATRA introduced intravenously into thebloodstream of animal models proved extremely toxic.There had to be a better way.
It consisted of wrapping the ATRA molecules inmicroscopic, injectable liposomes (averaging 3.1 micronsin diameter) to overcome this "ATRA resistance"occasioned by liver enzymes. and sustaining therapeuticlevels of the compound in the circulation.
The Houston inventors have patents pending on thisintravenous liposome formulation, jointly with Argus, towhich M. D. Anderson assigned exclusive developmentand marketing rights. Argus calls its proprietary L-ATRA(the liposomal formulation) product Tretinoin LF.
First Report Of Encapsulated ATRA In Humans
Hematologist Elihu Estey of M.D. Anderson announcedinterim results of their Phase I clinical trial yesterdayafternoon at the American Society of Hematologymeeting in Nashville, Tenn. Estey, the trial's principalinvestigator, told his audience at a session of theconference on leukemia that L-ATRA had achievedremissions in two of five PML patients, one of which hascontinued.
Blood levels have so far have been sustained for up to 85days. Also in this dose-escalation study, Argus's Cohensaid, "We will probably begin Phase II trials this month,without waiting to complete Phase I, because we believewe have already reached a tolerated dose well in excessof where we'll see activity."
The Phase I trial Estey reported on at Nashville involvedsome 35 patients with various blood-cell cancers whofailed previous conventional therapy, all treated at M. D.Anderson with the Argus L-ATRA product.
Phase II, Cohen said, "will be a multi-center, Argus-sponsored study, but strictly for assessing L-ATRA'sability to produce new remissions in promyelocyticleukemia patients who relapsed from prior treatment.."PML, he explained, "is a relatively uncommon disease,with 1,500 to 2,000 cases a year in the U.S."
The initial human study reported in Nashville, Arguspresident and CEO, David Leech, said, "presents a major`proof of concept' that we can overcome the drop inblood levels that accompanies oral administration and,potentially, greatly expand the utility of this compound."
A separate Phase II trial of L-ATRA, limited to Kaposi'ssarcoma (the leading cancer that affects AIDS victims) isabout to start under the auspices of Genzyme Corp. ThatCambridge-Mass. company just over a year ago invested$20 million in Argus. (See BioWorld Today, Sept. 13,1993, p. 1.)
"Genzyme is actually administratively running thatKaposi's trial," Cohen explained. The way our dealworks, Argus is conducting all of the leukemia work inthe U.S.; Genzyme, pretty much everything else in thiscountry." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.