By David N. Leff

Anticancer chemotherapy is a vital instrument in saving or prolonging the lives of people afflicted with neoplastic disease. But many patients prescribed this drastic drug treatment find the cure worse than the cause.

"It has been documented," observed cancer biologist Stephen Davis, "that some patients refuse chemotherapy because of the side effects - especially loss of hair. Some of them terminate therapy after a period of time because of their hair loss. It does have a tremendous impact on their psychological well being," he added, "and the stigma of a visual reminder when the patient goes out in public - advertising, and letting the world know that they are fighting cancer."

Davis is a senior research investigator at Glaxo Wellcome Research and Development in Research Triangle Park, N.C. "We've conducted market research," he said, "where we polled patients, nurses and oncologists. The key message from this data is that next to nausea and vomiting, patients rank hair loss as the most devastating of the treatment side effects. And at present we have no effective, preventive therapy."

Davis is senior author of a paper in today's Science, dated Jan. 5, 2001. Its title: "Prevention of chemotherapy-induced alopecia in rats by CDK inhibitors." The project marshaled 26 co-authors from seven cross-disciplinary departments at Glaxo: cancer biology, discovery genetics, molecular biochemistry, biometabolism research support, medicinal chemistry, structural chemistry and molecular sciences.

"We were able for the first time," Davis told BioWorld Today, "to target an enzyme, CDK2, in the mammalian hair follicle, which is a key switch for cell-cycle division. By blocking this switch, we were able to arrest that follicle cell and render it less sensitive to chemotherapy. The sensitivity of hair-follicle cells to antitumor agents relates to their state of proliferation.

"The reason we saw this as a valid approach," he went on, "is because cancer chemotherapy targets and kills rapidly dividing cells, which are hallmarks of malignant disease."

In Vitro, In Vivo, Compound Averted Alopecia

Davis and his co-authors racked up 29 different CDK2 small-molecule compounds, which inhibited that enzyme's stimulation of cell growth. "We synthesized them," he recounted, "to inhibit this effect, using structure-based approaches. After showing in an in vitro model that these inhibitors protected cells against a variety of chemotherapeutics, we went on to extend this observation into an animal model of chemotherapy-induced alopecia - CIA - and were able to generate some really fascinating and exciting data.

"Prior to chemotherapy," he recounted, "we pretreated rats and mice with topical applications of our best inhibitor compound. The data revealed quite convincingly that we were able to prevent chemotherapy-induced hair loss in this preclinical model.

"We studied two chemotherapy regimens," Davis continued, "that are used in the clinic, and which cause alopecia in patients. One was etopicide, a drug that treats a number of malignancies, including small-cell lung carcinoma and testicular cancer. Our selected compound stopped the drug's apoptosis in the hair follicles, and completely protected the treated scalp in about 50 percent of those animals, and an additional 20 percent had partial protection of hair at sites where we applied the inhibitor.

"The second antitumor regimen that we studied," he went on, "was cyclophosphamide-doxorubicin, a drug cocktail frequently prescribed to patients with advanced metastatic breast cancer. In this experiment, we observed complete protection of hair in 33 percent of the animals. This work," he went on, "was done in newborn rats, at an early age when they're actively growing their hair, because adult rats do not grow new fur."

Moving from rodent fur to human hair, Davis narrated, "We were able to take 1-centimeter-square fresh human scalp samples and xenotransplant them into the skin of immune-deficient SCID mice, which are incapable of mounting an immune response against foreign tissue. We grafted the skin on their backs by surgical implantation. Within two to three months we could observe actively growing hair - just like hair from a human being. The scalp samples," he hastened to explain, "were obtained from a plastic-surgeon's private practice.

"We set this model up so we could confirm the inhibitor's mechanism of action. We treated the area by a topical application and then assessed the state of cell division in the hair follicles. We could report that our compound arrested the epithelial cells for a temporary period of time, after which they were able to recover and reinitiate their division. This was exactly what we wanted to see - a reversible effect on cells in the hair follicle.

"CDKs - cyclin-dependent kinases - are a family of enzymes that control cell division," Davis explained. "We targeted the CDK2 enzyme, which participates in the process, from the cell cycle's late G₁ phase prior to initiation of DNA synthesis. We hypothesized that by inhibiting CDK2, we could block cell cycle progress at this point.

"When we started this project," Davis recalled, "we asked two very simple questions: Could we cause a transient cell cycle growth arrest in the hair follicle by delivering these CDK2 inhibitors? If so, could we make these cells less sensitive to chemotherapy - taking advantage of the basic fact that these cytotoxic drugs preferentially kill rapidly dividing cells?"

Not All Cells Divide At Any Speed

Asked how rapid is rapid, Davis responded, "Typically, at 18 to 24 hours you'll find cells capable of dividing from start to finish. Most cells in organs are not dividing at all," he pointed out, "unless you're targeting the hair follicles or bone marrow or intestinal tract. Those organs have a population of cells that are rapidly dividing, and as a result chemotherapy also induces toxic side effects in the gut, notably the damage of mucositis."

Glaxo has not yet extended its hair loss side effect to the gut wall, but, Davis allowed, "we have definitely considered taking this approach to other tissues." His Science paper concludes, "On the basis of the evidence presented here, clinical trials in cancer patients to assess the efficacy of this approach to prevent chemotherapy-induced alopecia may be warranted."