For mice, as for people, spontaneous metastasis of a solid tumor tointernal organs of the body is a sentence of death.
Yet five of 12 mice treated for spread of their cancers to the liversurvived to the ripe old murine age of 180 days since receiving theirexperimental therapy _ long enough to be considered "cured."
These lucky rodents owe their lives to a gun that shoots goldenbullets.
An explosive burst of helium gas propelled these auric pellets down atube and into the rodents' shaved abdominal skin. There, the tinyprojectiles released a plasmid payload. It delivered a cDNA genesequence encoding high-level expression of a murine cytokine,interleukin-12.
Just below this forced entry into the epidermis lay a murinemastocytoma, of which researchers had seeded one million cells intothe animals subcutaneously, 12 days earlier. Eleven control rodents,into which the gene gun had transfected a dummy cDNA, died ofmetastases within a month, even after excision of their primarytumors 12 or 15 days following the IL-12 gene therapy.
A paper in the current Proceedings of the National Academy ofSciences (PNAS), dated June 25, 1996, reports this in vivoexperiment under the tell-all title: "Gene-gun-mediated skintransfection with interleukin-12 gene results in regression ofestablished primary and metastatic murine tumors."
Its principal author is molecular oncologist Ning-Sun Yang, directorof cancer gene therapy at the newly-founded Auragen Inc, inMiddleton, Wisc., and adjunct professor at the University ofWisconsin in Madison. Medical doctor and post-doctoral cancerimmunologist Alexander Rakhmile-vich is the article's first author.
"All of the work in this PNAS paper," Yang told BioWorld Today,"was carried out in our laboratory at the gene-therapy company calledAuragen. In the past two months we split off from our former parentcompany, Agracetus Inc., here in Middleton, which for almost tenyears has been part of W. R. Grace & Co. [of Boca Raton, Fla.] Now,Auragen is owned 100 percent by Grace, as its subsidiary for genetherapy."
Agracetus was an early developer of biolistics _ gene-guntechnology
Besides Auragen's rescue of metastatic mice, it conducted in vivogene-gun trials of treating half a dozen different primary murinetumors _ a carcinoma, two sarcomas, a melanoma, a lymphoma, andthat mastocytoma.
"Only one to four treatments with IL-12 cDNA-coated particlesstarting on day seven after tumor-cell implantation," Yang andRakhmilevich reported, "were required to achieve complete tumorregression . . . or suppression of tumor growth in four tumor models.
"When we dealt with the six tumor models," Rakhmilevich toldBioWorld Today, "the established solid tumors completely regressedin four models. These mice didn't develop secondary tumors."
In each of two tumor types, seven of eight mice regressed completely;in two others, four of seven and three of eight.
"A challenge experiment with a second dose of the same tumor,"Rakhmilevich added, "showed that these mice had developedimmunological memory, so were immune to their specific tumors."
Yang added that "Most human tumors are not immunogenic. So thereare things to be done in the future to further develop this, and seehow to make use of it."
"Remarkably," the co-authors observed, "the local amount ofdetectable IL-12 at the [gene-gun] treatment tissue site is 1/400 to1/40,000 of the dosage of [systemic] recombinant IL-12 proteinemployed for efficacy studies in the same or similar mouse tumormodels.
"Systemic [rather than local] administration of recombinant IL-12caused dose-dependent toxicity in mice and humans," the PNASarticle pointed out. It added: "Thus, a delivery mechanism [i.e.,Auragen's gene-gun] that can provide relatively low levels of IL-12at the target tissue might be advantageous in that it could generate anantitumor effect without causing systemic toxicity."
Since submitting their article to PNAS some months ago, Yang andhis co-author "have done some comparative studies, with IL-12versus different cytokines, and tried some of the latter in largeranimal models, for instance, dogs."
The team hopes to apply its approach to melanoma human cutaneousand subcutaneous tumors, "not immediately but not 10 or 20 yearsfrom now either; rather, in some-mid-range future," Yang concluded.n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.