By David N. Leff

Editor¿s note: Science Scan is a roundup of recently published biotechnology-relevant research.

Sales of recombinant human erythropoietin (rhEPO) last year by Amgen Inc. total billions of dollars. The company¿s block-busting cloned drug ¿ under the trade names Epogen and Procrit ¿ started out in the 1980s to treat the anemia of end-stage kidney disease and accompanying dialysis. Since then, its indications have extended to anemia of AIDS and of certain cancers.

Also, on the side, an underground market for EPO developed among athletes, such as endurance bike racers. The hormone provided them a blood-boosting burst of energy. It also cost the life of at least one Dutch bike racer from kidney failure due to EPO overdose. But unlike other illicit anabolic fixes, which could be detected in contestants¿ urine, EPO, being a totally natural product of the body, evaded detection.

When the blood¿s cargo of oxygen dips, the kidneys sense this O2 deficit and release erythropoietin. This recruits stem cells in the bone marrow, which stimulates the output of O2-rich red blood cells (RBCs) to fuel the body¿s energy needs. So far, EPO¿s therapeutic role has been limited to countering anemia and the concomitant paucity of RBCs.

Now research immunologists at the Weizmann Institute of Science in Rehovot, Israel, announce a new and unsuspected property of EPO ¿ combating malignancy itself. Their paper in the Proceedings of the National Academy of Sciences (PNAS), dated April 24, 2001, bears the title: ¿Erythropoietin induces tumor regression and antitumor immune responses in murine myeloma models.¿

The human multiple myeloma (MM) that their mice modeled is an uncommon malignant neoplasm more frequent in men than women, marked by anemia, hemorrhage, frequent infections and weakness. It arises in bone marrow, mainly involves the skeleton, and in late stages metastasizes to a variety of organs. Most patients die of MM in 15 to 48 months. Sixty percent to 90 percent of them develop anemia, largely due to deficient production of erythropoietin.

The co-authors hypothesized that, ¿in addition to the correction of anemia, EPO may have an additional, unrecognized biological effect on the disease.¿ The mouse model of MM they tested ¿resembles the human disease in several aspects: spontaneous origin in the bone marrow, monoclonal gammopathy [excessive output of immunoglobulin M], and osteolytic bone lesions and destruction.¿

They challenged 150 of these rodents by injecting 10,000 growing MM tumor cells under their skin, then treated them systemically with EPO. The result: ¿permanent and complete tumor regression in 30-60 percent of the EPO-treated mice.¿ Over a 12-month follow-up period, only three of 20 animals developed recurrent tumors. Of 100 control mice, zero to 10 percent experienced spontaneous tumor regression.

¿The main finds of the present research,¿ the PNAS paper concludes, ¿are that EPO, besides its known activity on the erythroid lineage, induces tumor regression by promoting an effective antitumor immune response.¿ It added: ¿How EPO mediates its effects has not yet been elucidated fully.¿

Why And How p53 Goes From Its Mission Control In Nucleus To Crash In Cytoplasm

About half of all human cancers harbor a tumor suppressor oncogene, p53 by name, that isn¿t up to its job. Its protein normally monitors biochemical signals that report the occurrence of DNA damage ¿ for example, ultraviolet radiation ¿ or of mutations implicated in tumor development. When p53 receives such signals, it circles its wagons in the cell¿s nucleus, by taking on a phosphate. In the nucleus, it¿s poised to impose one of two measures: program the threatened cell to self-destruct, or arrest its growth cycle.

When a normal, healthy cell is happily dividing, it has no need of p53¿s good offices. In fact, quite the opposite, intrusion of that potent oncogene where it¿s not wanted, can damage cell division. Therefore, p53 moves out of its digs in the nucleus, and shifts to the cell¿s cytoplasm. There it takes itself out of the way by breaking up or self-destructing.

A paper in Science dated June 8, 2001, reports new data elucidating this complex double gig of p53 ¿ on standby to protect against the threat of malignancy, and removing itself from the scene when appropriate. The article is titled: ¿A p53 amino-terminal nuclear export signal inhibited by DNA damage-induced phosphorylation.¿

Its authors, scientists at the University of North Carolina¿s Lineberger Comprehensive Cancer Center, have discovered an amino acid sequence within p53 that is responsible for transporting the protein from its watchtower in the cell nucleus to its cytoplasmic finis. They observe, ¿This represents one of the first examples where a nuclear exporting signal can be regulated by phosphorylation.¿

They add, ¿If we were to develop a compound to block p53 export, we might be able to restore p53 function in tumor cells with mutated kinase genes. We could give the compound to patients, to wake up the p53 or prevent its degradation.¿

Anti-Leukemia Drug Achieves Unexpected Remissions In Phase I Clinical Trial

Adult acute leukemia is another bad rap. Three in 10 patients do not achieve complete remission. When a patient in his 60s or 70s is newly diagnosed, his chance of surviving five years is less than 20 percent. Traditional treatment usually involves chemotherapy, radiation, perhaps a bone marrow transplant.

A new, experimental antileukemia drug, code-named R115777, is given in pill form. Scientists at the University of Rochester, N.Y., recently administered it to 34 leukemia patients in a Phase I trial. Thirty percent of them went into partial or complete remission. R115777 was developed and funded by Janssen Research Foundation, of Beerse, Belgium.

An article in the journal Blood, dated June 1, 2001, reports the study under the title: ¿Clinical and biologic activity of the farnesyltransferase inhibitor R115777 in adults with refractory and relapsed acute leukemias: a phase I clinical laboratory correlative trial.¿

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