A cancer cell can live forever. It owes this undyingaptitude for survival to the evasion and avoidance ofapoptosis, which persuades cells to end it all byprogrammed suicide.
Apoptosis is one of nature's favorite ways to kill off cellswhose mission in life is over. Thus, certain tumor-suppressor proteins, notably p53, can induce some cancercells to go the programmed cell-death route. By thecontrary token, an oncogene such as c-myc can put areverse spin on this p53 process by detouring from theapoptotic pathway to the fast lane of malignantimmortality.
A recently unmasked ring-leader in the anti-cell-suicide,pro-tumor-life movement is a family of genes denotedbcl-2. Many a cancer over-expresses a member of thisapoptosis-inhibiting group of DNA sequences, which co-conspire with the c-myc oncogene.
But, as Isaac Newton postulated in another arena, "Toevery action there is always opposed an equal reaction."
In the case of cancer, one such contrarian promoter ofprogrammed cell death is a variant of the bcl-2 gene,bclxs by name. Pathologist and molecular biologistGabriel Nu ez cloned it in the last two years at theUniversity of Michigan. He and oncologist MichaelClarke are principal co-authors of a paper in the currentProceedings of the National Academy of Sciences(PNAS) dated Nov. 21, 1995. Its title: A recombinant bcl-xs adenovirus [AV] selectively induces apoptosis incancer cells but not in normal bone marrow cells."
"Basically, what we did," Clarke told BioWorld Today,"was make an AV vector that expresses the bcl-xs gene.This represses bcl-2 family members, which affect theprogrammed cell death pathway."
They found that "tumors derived from solid tissues, forexample, breast cancer, seem to require expression of abcl-2 gene to maintain viability."
Next, the Michigan team "looked at normal bone marrowstem cells, which give rise to all the blood elements, tosee if the virus had any effect on them. It didn't."
They reported that mice irradiated to kill off their bloodcells' progenitors, then exposed to the recombinant viralvector, successfully repopulated their purged bonemarrow.
Clarke continued: "Once we found we could use the viralvector to very effectively kill tumor cells that werecontaminating the bone marrow, we saw that practicallythat could be used for patients undergoing high-dosechemotherapy and bone marrow transplantation."
This ex vivo procedure is employed largely for adultswith breast cancer and children with neuroblastoma."Neuroblastoma," Clarke explained, "is the commonestsolid tumor in children. It's uniformly lethal, but unusual,with only about 500 cases a year. Half of these are treatedby autologous bone marrow transplantation, to rescuetheir stem cells from high-dose chemotherapy. Probablyall of these transplanted cells are contaminated withtumor."
He and his co-authors intend to start ex vivoneuroblastoma trials of their bcl-xs AV vector counter-measure therapy "as soon as we get the FDA toxicity datadone." Clarke added that he is also in discussions withseveral companies seeking funding of up to $500,000 forthe trials.
Meanwhile, nude mice at Michigan are standing in forfuture in vivo therapeutic trials against human breastcancer. The immunity-lacking animals, carryingimplanted human tumors, will receive bcl-xs vectortreatment systemically, Clarke said.
This preclinical work builds on in vivo destruction ofbreast cancer cells described in the PNAS paper."Primary carcinoma cells, as well as cell lines derivedfrom solid tumors, rapidly underwent cell death afterinfection with the bcl-xs adenovirus," it reported.
Meanwhile, Clarke and his co-authors are busy filling inthe outstanding blanks of knowledge concerning theirnew-found bcl-xs adenovirus anti-cancer weapon:
* Since reporting that mammary, colon, gastriccarcinomas and pediatric neuroblastomas are susceptibleto the vector, they have extended the list of solid-tumortargets, with publication now pending.
* Just what makes these malignant tissues selectivelysusceptible to the vector is a question "we'll probably beable to answer within a year," Clarke said. "We'restudying that, and are three-fourths of the way there."
* Conversely, the property that makes hemopoietic stemcells in bone marrow resistant to the adenovirus is closerto elucidation. "That's what I'm doing here," said Clarke,who is on sabbatical leave at Stanford University. "We'llsoon know the answer to that at least partly. We'reputting out a paper on it in the next couple of weeks." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.