Novel, Even Unlikely, Drugs May Curb Childhood Leukemia, According to Recent Studies at The Children's Hospital of Philadelphia

05/14/2001

PHILADELPHIA, May 14 /PRNewswire/ -- While survival rates for childhood leukemias have soared in the past 30 years, about a quarter of pediatric cases remain stubbornly resistant to treatment. As a new attack strategy, scientists are adapting recent discoveries about cell development to coax leukemia cells back to normal growth patterns or to trick them into committing suicide.

"Reaching the next level of leukemia treatment will require many new approaches that draw upon our expanding knowledge about how healthy cells differentiate during normal growth and development," said Beverly Lange, M.D., director of experimental therapeutics within the Division of Oncology at The Children's Hospital of Philadelphia, who is an expert in these new attack strategies.

Unlike conventional cancer drugs, the newer drugs are based on detailed knowledge of cellular mechanisms that can be used to manipulate cancer cells in a way that is gentler to surrounding healthy cells.

Oncologists at Children's Hospital are investigating a number of novel, even unlikely, drugs as highly specific, less toxic weapons against childhood leukemia. For example:

-- A form of vitamin A is being used to reprogram a cancer cell into becoming a harmless, normal white blood cell.

-- Borrowing from its use in traditional Chinese medicine, carefully controlled doses of arsenic can trigger cancer cells to commit suicide by mimicking the normal developmental process of "apoptosis," or programmed cell death.

-- A new type of leukemia drug, the bioengineered compound Glivec, can block the genetic signals that direct cancer cells to grow, while leaving normal cells largely unharmed.

-- The naturally occurring protein interleukin-2 may kick-start the body's immune system to better fight leukemia.

Taming cancer cells Some experimental new treatments rely on methods that neutralize or disrupt cancer cells rather than killing them outright in a frontal attack. "Most conventional cancer drugs rely on lysis, in which a direct attack by the drug causes the cancer cell to burst and die," Dr. Lange explained. But cells may also die through indirect methods that target cancer cells while sparing normal cells.

One such method is terminal differentiation, in which a cell enters a mature stage, with a limited lifespan. For example, all-trans-retinoic acid, a form of vitamin A, is used in this way against the diseased blood cells found in acute promyelocytic leukemia (APML). Rather than directly killing the cancer cell, all-trans-retinoic acid forces the cell to differentiate into a mature white blood cell by reprogramming its genetic mechanisms. It redirects the cancer cell into behaving like a normal blood cell rather than an immortal, constantly dividing cancer cell. "At the same time it dooms the cell, because mature white blood cells live for only 12 hours," said Dr. Lange.

Arsenic and cell suicide When all-trans-retinoic acid does not work against APML, low doses of arsenic may be helpful, using a different cellular mechanism. By targeting a receptor on the surface of the cancer cell, arsenic triggers the process of "apoptosis," or programmed cell death.

This suicide apparatus resides in all cells as a set of proteins that remain dormant until set in motion by molecular signals specific to each type of cell. In early embryonic development, apoptosis sculpts tissues by eliminating unneeded cells. Throughout life, it serves to destroy diseased or nonproductive cells. However, cancer cells may fail to respond to apoptosis signals and become immortal and deadly.

Arsenic can reset the genetic machinery, permitting apoptosis to seal the fate of cancer cells. At the same time, the low dose of arsenic spares healthy cells. Both arsenic and all-trans-retinoic acid are derived from compounds used in traditional Chinese medicines. "Although APML is a relatively rare disease," said Dr. Lange, "these treatments may be useful in other cancers as well."

Blocking cancer signals News reports over the past year have heralded highly encouraging results from clinical trials of Glivec (STI-571) for adults with chronic myeloid leukemia (CML). Glivec represents a new class of drugs called signal transduction inhibitors that block the signaling pathways that cause cancer cells to grow. It is bioengineered to zero in on a cell receptor present in leukemia cells that carry a genetic defect called the Philadelphia chromosome.

This targeted approach causes minimal side effects to healthy tissue. While CML is rare in children, the same genetic defect found in CML, the Philadelphia chromosome, occurs in an aggressive form of childhood acute lymphoblastic leukemia (ALL).

Directed by Dr. Lange, Children's Hospital is testing Glivec against that treatment-resistant form of ALL. Through its participation in the Children's Oncology Group, a collaborative national organization that pools data and expertise from many cooperating cancer centers, Children's Hospital is currently conducting pediatric trials of the drug. Because studies have suggested Glivec may have wider applications against other types of cancer, Children's Hospital will test it later this year in children with highly malignant brain tumors.

Boosting immune effects Also under the umbrella of the Children's Oncology Group, Dr. Lange is leading tests of interleukin-2 (IL-2), a compound that occurs naturally in the body. IL-2 is an immune system protein that plays an important role in an immune response that occurs after a bone marrow transplant. In the "graft vs. leukemia effect," IL-2 stimulates the body's natural killer cells to attack leukemia cells and drive the disease into remission.

The pediatric clinical trials led by Dr. Lange will test whether providing IL-2 can confer this benefit against acute myeloid leukemia (AML) in the absence of a marrow transplant. If so, said Dr. Lange, the approach may help children with AML who do not have a sibling donor for a transplant.

FACTS

CHILDHOOD LEUKEMIA

Leukemias are cancers that affect the blood and the blood-forming tissues, including the lymphatic system and the bone marrow. In all leukemias, abnormal cells multiply and crowd out healthy cells. The disruption of normal blood cell function leaves patients vulnerable to infections. Leukemia cells accumulate in and damage organs such as the liver, spleen and lymph nodes.

Leukemias are grouped into acute and chronic categories, depending on the speed of progression. They are further classified by the type of cell involved.

Acute lymphoblastic leukemia (ALL) is the most common childhood leukemia. It involves uncontrolled growth of lymphoblasts, the immature cells that normally develop into lymphocytes, which are white blood cells that play essential roles in the immune system. Cure rates for ALL have improved dramatically, from below 5 percent in the early 1960s to nearly 80 percent today, although particularly aggressive types of ALL remain, such as a form associated with the Philadelphia chromosome.

The Philadelphia chromosome is an abnormal transfer of genetic material between chromosomes 9 and 22 (a translocation). The chromosome defect stimulates the growth of particular types of leukemia cells. It is associated with nearly all cases of CML and with smaller proportions of ALL. The defect was discovered in 1960 by Philadelphia researchers Peter Nowell and David Hungerford.

Acute myeloid leukemia (AML) involves uncontrolled growth of nonlymphoid blood cells, most commonly immature cells called myeloblasts or monoblasts. While more common in adults, AML may occur in teenagers and younger children.

Acute promyelocytic leukemia (APML or APL) affects promyelocytes, cells that develop from myeloblasts and which normally become white blood cells. APML is rare in both children and adults.

Chronic myeloid leukemia (CML) usually progresses gradually and involves overproduction of granulocytes, which are immune system cells. Much more common in adults than in children, CML usually involves a genetic defect called the Philadelphia chromosome.

STI-571 (trade name, Glivec) is a signal transduction inhibitor, one of a class of drugs designed to interfere with signaling pathways in cells. It is genetically engineered to target a cell receptor present in leukemia cells that possess the Philadelphia chromosome. It blocks signals that stimulate the growth and production of other leukemia cells. Because it is specific for one genetic defect, the drug has few side effects on healthy cells. STI-571 has been tested successfully in adults with CML, and is being tested against certain types of childhood ALL.

CONTACT: John Ascenzi of The Children's Hospital of Philadelphia, 215-590-7332 or ascenzi@email.chop.edu.