NEW YORK CITY-The antisense agent Genasense (formerly known as G-3139) may offer a promising new approach for the treatment of hormone-refractory prostate cancer, according to data presented here at the most recent Chemotherapy Foundation Symposium by Anthony W. Tolcher, MD, Clinical Assistant Professor of Medicine at the University of Texas Health Science Center and Associate Director of Clinical Research at the Institute for Drug Development in San Antonio.
In a Phase I study, Genasense was administered in combination with docetaxel and demonstrated at least a 50% reduction from baseline in prostate-specific antigen (PSA) that lasted at least four weeks in seven of 12 patients with hormone-refractory prostate cancer not previously treated with taxanes.
In addition, two patients had more than a four-fold reduction in PSA, and three others had lesser reductions in PSA. Objective responses were also observed.
The idea behind the combination is that Genasense, an antisense oligonucleotide specific for bcl-2, would inhibit this protein, and thereby enhance the antitumor activity of docetaxel, Dr. Tolcher explained.
Bcl-2 has also been implicated in androgen-dependent growth of prostate cancer and intrinsic resistance to chemotherapy associated with hormone-resistant prostate cancer.
Bcl-2 protein is overexpressed in the majority of pathologic specimens of patients with hormone-refractory prostate cancer, Dr. Tolcher said. The bcl-2 protein confers resistance to several pro-apoptotic stimuli, including hormone-, radio- and chemotherapy.
In vitro, the inhibitory concentration 50 percent (IC50) of docetaxel shifts to the left by approximately 10-fold when cells are treated with antisense compounds directed to inhibit bcl-2.
Animal studies have shown that Genasense plus docetaxel-treated mice with the prostate cancer PC3 tumor line survived beyond 60 days (long term). No long-term survivors were found in the other treatment regimens groups-saline control, Genasense alone, and docetaxel alone.
In the Phase I trial, toxicity was standard for what one would usually see with docetaxel alone, Dr. Tolcher said, and included alopecia, transient neutropenia, and nail changes. A constellation of mild, nonhematologic toxicities of low-grade fevers without rigors, diuresis, and fatigue was seen during Genasense infusion.
Phase II Trial
Based on impressive activity and tolerability seen in the ongoing Phase I study, a multicenter Phase II study has been initiated. Genasense is being developed as an intravenous drip infusion for the potential treatment of various cancers including melanoma, prostate, breast, and colon.
Hematologic Malignancies
The ability of antisense to block bcl-2 and thereby boost chemotherapeutic activity and induce cancer cell death has been tested and found to be encouraging in hematologic malignancies, as well.
According to Michael R. Grever, MD, Chair and Professor in the Department of Internal Medicine and Associate Dean for Medical Services at Ohio State University Health Sciences Center in Columbus, bcl-2 is expressed in many different types of tumors including hematologic malignancies.
He cited several studies in hematologic malignancies. In acute myelogenous leukemia (AML), the combination of gemtuzumab ozogamicin (Mylotarg) and antisense substantially increased the induction of apoptosis over gemtuzumab ozogamicin alone.
Chronic lymphocytic leukemia (CLL) cells show a substantial decrease in viability when exposed to the combination of antisense and fludarabine compared with fludarabine alone.
In multiple myeloma, when antisense is combined with dexamethasone, the viability of cancer cells is markedly decreased compared with the use of dexamethasone alone.
In a study of Genasense plus FLAG chemotherapy (fludarabine, Ara C, and granulocyte colony-stimulating factor) in acute leukemia by Marcucci et al, seven of 20 patients (35%) achieved complete remission. Two have been in complete remission for more than a year. Patients in this study were either primary refractory or in relapse.
Preclinical studies provide a substantial rationale to look at antisense in combination with a whole host of mechanistically different therapeutic strategies for treating hematologic malignancies, Dr. Grever stated. Although some reduction in platelet counts during infusion has been seen in Phase I studies, the counts revert to normal after infusion.
Combined with laboratory data, early results from several clinical trials have demonstrated proof of principle, and offer encouragement that this approach makes sense biologically, Dr. Grever concluded.
Film Helps Patients Prepare for BMT
The New Normal: Life After Bone Marrow/StemCell Transplantation, a film recently released by the National Bone Marrow Transplant Link (nbmtLINK), tells the stories of six bone marrow transplant survivors, their families, and caregivers. With its judicious combination of hope and realism, the film is a valuable tool for patients about to undergo the procedure.
The patients, a varied group ranging from being two to 10 years post-op, recount their stories from diagnosis to transplant to their new normal lives today. Without overlooking the difficulties and complications of the experience, the film's overall message is one of encouragement.
The idea for the film came from Harry Pierce, the former Vice Chair of General Motors and a transplant survivor. We agreed that it would be a worthwhile project and he said that General Motors would make it happen, recalled Myra Jacobs, Executive Director of nbmtLINK. GM underwrote the cost of production and paid for 5,000 free video copies of the 46-minute film for distribution to patients, health professionals, and major transplant centers.
One of the most moving stories is that of a young man of limited financial resources whose church contacted another congregation in Ann Arbor, where his surgery was performed. The church members there provided round-the-clock care for him throughout his hospitalization.
We didn't produce this film to explain the procedure, but rather to reduce peoples' fears and encourage them to have hope, Ms. Jacobs said.
It is a life-changing experience is the way one of the patients described it. It's hard to believe that you will grow from this and that the change could be positive, but it is.
Copies of The New Normal may be obtained by calling nbmtLINK at (800) 546-5268 or sending an e-mail to nblink@aol.com.
© 2002 Lippincott Williams & Wilkins, Inc.