AML

לאבי בן 72 נתגלה לוקמיה מילואידית חריפה. הוא מקבל טיפול כימותרפי. מה סיכויי ההצלחה? האם קיימות תרופות חדשות למחלה? תודה

שלום לך, AML היא לצערנו מחלה קשה ביותר לריפוי ולרוב הפרוגנוזה אינה טובה. עם זאת כדאי אולי לבדוק את הדברים הבאים: 1. ויטמין D3 Antiproliferative Effect of Vitamin D3 Anlaog in Hematologic Malignancies Hematologic malignancy including acute myelogenous leukemia (AML) represents a hemtopoietic stem cell disorder representing a block in differentiation into mature cells. High-dose chemotherapy has improved survival of patients with hematologic malignant disease, but severe bone marrow suppression limits its clinical use. An alternative therapy for these patients is to induce differentiation and/or inhibit clonla proliferation of malignant cells without toxic effects on their normal hematopoietic stem cells. The seco-steroid hormone, 1,25 dihydroxyvitamin D3 [1,25(OH)2D3], has an inportant role in the maintenance of calcium homeostasis through binding to specific intracellular receptors. The classical target organs of this seco-steroid are the interstine, bone AND kieney. A variety of tissues that do not participate in mineral AND bone metabolism also possess specific receptors for AND respond to 1,25(OH)2D3 including normal AND neoplastic hematopoietic cells. The 1,25(OH)2D3 induces AML cell lines as well as blast cells from AML patients to differentiate into mature cells AND inhibits their proliferation in vitro AND in vivo without suppression of normal granulocyte-monocyte committed stem cells. However, it can not be used in clinical trial because of development of major side effects, hypercalcemia. Therefore, research activities have been directed at finding potent analogs of 1,25(OH)2D3 with a more favorable therapeutic profile. We have examined more than 200 analogs to find potent viatmain D3 analogs. EB1089 is a novel 1,25(OH)2D3 analog that has more potent antitumor properties with reduced hypercalcemic effects in vitro AND in vivo. Antitumor effects of EB1089 has been proven in a vareity of solid tumors including prostate cancer AND breast cancer. We have extented our experiments to its antiproliferative AND bilogical effects on hematologic malignancies, especially AML AND multiple myeloma. In addition to antiproliferative effects, we have investigated its mechamisms regardign cell cycle AND apoptosis. Finally, we will try this analog in hematopoietic stem cell transplantation. ******************************************************************************************* Effect of a vitamin D3 analoge, EB1089, on hematopoietic stem cells from normal AND myeloid leukemia blasts (Leukemia 1996;10,1751-1757) The sero-steroid 1,25 dihydroxyvitamin D3 (1,25(OH)2D3) induces differentiation AND inhibitor clonal proliferation of HL-60 cells. We analyzed the effect of a noval vitamin D3 analog, EB1089, on normal myeloid AND leukemic cells as well as CD34+ cells. EB1089 showed an extraodinary inhibition of clonal growth of HL-60 cells(ED50=5x10-11M) AND AML blast cells (ED50=9x10-10M) compared to 1,25(OH)2D3 without suppression of growth of normal human bone marrow CFU-GM. The CD34 cells from acute myeloid leukemia(AML) blasts were inhibited in a dose-dependent fashion by 1,25(OH)2D3 with an ED50 of 1.2x10-9M; AND even more strikingly, 10-10M of EB1089 inhibited all clonal growth of human CD34+ leukemic clony-forming cells. In contrast, both EB1089 AND 1,25(OH)2D3 (10-8M) showed little per only mild inhibition of CD34+ clongenic hematopoietic cells from normal human peripheral blood(PB); AND in liquid culture, EB1089 stimulated the proliferation of normal human CD34+ cells about 2.5 times as compared to control cultures. In order to evaluate the potential use of EB1089 for purging leukemic cells from normal CD34+ progenitor cells for PB stem cells transplantation (PBSCT), normal human PB mononuclear cells(PBMNC) were contaminated with HL-60 cells, AND then CD34+ cells purified AND treated with EB1089. We found that CD34+ purificated AND EB1089 purging was able to eliminate approximately 100% of HL-60 leukemic cells with no toxicity to normal CD34+ hematopoietic progenitor cells. These data suggested that purification of CD34+ cells AND ex vivo treatment with EB1089 might provide an effective therapeutic approach for PBSCT. ******************************************************************************************* 2. Telomerase Telomerase activity in acute myelogenous leukemia: clinical AND biological implications (British Journal of Haematology 1998. 100, 156-165) We examined telomerase activity in myeloid leukaemic cell lines, normal haemopoietic cells, AND leukaemic blasts from acute myelogenous leukaema (AML) patients. Normal bone marrow mononuclear (BMNC) cells expressed low telomerase activity was detected in 10 myeloid leukaemic cell lines compared to normal BMNC cells. Treatment with 1,25(OH)2D3, AND vitamin D3 analogues, EB1089 AND KH1060, reduced telomerase activity in vitamin D3-sensitive HL-60 cells. whereas vitamin D3 insensitive K562 cells did not change its activity. This down-regulation of telomerase activity by EB1089 was associated with induced of p21 protein. The rank order of telomerase activity was leukaemic CD34- cells> leukaemic CD34+ cells> normal CD34- cells> normal CD34+ cells. Telomerase activity was posotive in all of the AML patients tested: however, heterogeneity of telomerase activity was found amongst this group. Therefore we compared telomerase activity with clinical response. Unexpectedly, we found that a higher rate of complete remission was noted in AML patients with higher telomerase activity. No associated between telomerase activity AND biological parameters including percentage of S-phase, cytotoxicity to cytosine arabinoside AND percentage of CD34+ cells in AML blasts was found. These results suggest that telomerase activity in AML patients is detected with high frequency, but is heterogenous. Expression level of telomerase activity may have a clinical implication in AML patients regarding clinical response ****************************************************************************************** 3. סטטינים (תרופות להורדת כולסטרול) אני הייתי שוקל לשלב אותן עם מעכבי COX2 וויטמין D Health Headlines Sources: Reuters | AP | ABCNEWS.com | HealthSCOUT Thursday July 26 6:03 PM ET Cholesterol Drug Slows Leukemia Cell Growth in Lab NEW YORK (Reuters Health) - A drug used to lower cholesterol appears to slow the growth of laboratory-grown leukemia cells, researchers report It is not yet clear if the drug would help leukemia patients, but the findings ``may open new avenues in both the laboratory AND clinical research of the treatment of leukemia,'' according to Dr. Michael Lishner AND colleagues from Tel-Aviv University in Israel. According to their preliminary study findings, the cholesterol-lowering drug simvastatin slowed the growth of cells of a type of cancer known as acute myeloid leukemia (AML). And when combined with cytosine arabinoside (ARA-C)--a chemotherapy drug frequently used to treat AML--cancer cell growth was inhibited even further, the investigators report in the July issue of the Journal of Investigative Medicine. AML is a rapidly progressing AND often fatal disease in which too many immature white blood cells accumulate in the blood AND bone marrow. The study findings suggest that simvastatin might allow patients to benefit from lower doses of ARA-C, which can have toxic side effects. At this point, however, it is not clear how simvastatin inhibits leukemia cell growth. The researchers note that leukemia cells need increased concentrations of cholesterol to reproduce, AND simvastatin lowers cholesterol in the blood by inhibiting a key enzyme involved in cholesterol production. Further research is needed to look at the effects of the cholesterol-lowering drug in patients with AML, Lishner AND colleagues suggest. SOURCE: Journal of Investigative Medicine 2001;49:319-324 ******************************************************************************************* Blood 1999 Feb 15;93(4):1308-18 Increased sensitivity of acute myeloid leukemias to lovastatin-induced apoptosis: A potential therapeutic approach. Dimitroulakos J, Nohynek D, Backway KL, Hedley DW, Yeger H, Freedman MH, Minden MD, Penn LZ Department of Cellular AND Molecular Biology, Ontario Cancer Institute, Toronto, Ontario, Canada. We recently demonstrated that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme of de novo cholesterol synthesis, was a potential mediator of the biological effects of retinoic acid on human neuroblastoma cells. The HMG-CoA reductase inhibitor, lovastatin, which is used extensively in the treatment of hypercholesterolemia, induced a potent apoptotic response in human neuroblastoma cells. This apoptotic response was triggered at lower concentrations AND occurred more rapidly than had been previously reported in other tumor-derived cell lines, including breast AND prostate carcinomas. Because of the increased sensitivity of neuroblastoma cells to lovastatin-induced apoptosis, we examined the effect of this agent on a variety of tumor cells, including leukemic cell lines AND primary patient samples. Based on a variety of cytotoxicity AND apoptosis assays, the 6 acute lymphocytic leukemia cell lines tested displayed a weak apoptotic response to lovastatin. In contrast, the majority of the acute myeloid leukemic cell lines (6/7) AND primary cell cultures (13/22) showed significant sensitivity to lovastatin-induced apoptosis, similar to the neuroblastoma cell response. Of significance, in the acute myeloid leukemia, but not the acute lymphocytic leukemia cell lines, lovastatin-induced cytotoxicity was pronounced even at the physiological relevant concentrations of this agent. Therefore, our study suggests the evaluation of HMG-CoA reductase inhibitors as a therapeutic approach in the treatment of acute myeloid leukemia. ******************************************************************************************* 4. Bufalin וויטמין A Leuk Res 1998 Jul;22(7):589-95 Enhancement by bufalin of retinoic acid-induced differentiation of acute promyelocytic leukemia cells in primary culture. Yamada K, Hino K, Tomoyasu S, Honma Y, Tsuruoka N Department of Hematology, Showa University School of Medicine, Shinagawa, Tokyo, Japan. Bufalin, a cardiotonic steroid isolated from the Chinese toad venom preparation Chan'su, has differentiation-inducing activity in several myeloid leukemia cell lines. We examined the effect of bufalin on differentiation of leukemic cells from acute myeloid leukemia (AML) patients in primary culture. Bufalin significantly stimulated functional AND morphologic differentiation of leukemia cells in four of 20 cases, suggesting that bufalin alone is only a modest inducer of differentiation of AML cells in primary culture. In contrast, acute promyelocytic leukemia (APL) cells showed synergistic differentiation after treatment with all-trans retinoic acid (RA) AND bufalin. In some cases, bufalin restored RA sensitivity to previously resistant APL cells. The effective concentration of bufalin for differentiation-inducing activity in APL cells was lower than for its cardiac action. Combined treatment with bufalin AND RA may be more effective than RA alone in differentiation therapy of APL. **************************************************************************************** 5. התרופה החדשה יחסית Mylotarg By Judy Peres Chicago Tribune Staff Writer May 19, 2000 The Food AND Drug Administration on Thursday granted fast-track approval to the first of a new class of cancer drugs that use synthetic antibodies like guided missiles to deliver a payload that targets cancerous cells while largely sparing normal ones. These new agents have the potential to knock out tumors without the grueling side effects of traditional chemotherapy, which sometimes makes patients sicker AND can be fatal. They are part of an ongoing revolution in the development of cancer treatments made possible by new insights into the biology of the disease AND by technological advances in researchers' ability to manipulate molecules. Mylotarg, the drug approved Thursday, is used to treat a virulent blood cancer called acute myeloid leukemia, OR AML, which strikes about 10,000 Americans a year. The drug, made by Wyeth-Ayerst Laboratories, was tested in 142 AML patients whose cancer had gone into remission after chemotherapy but later had relapsed. Mylotarg was able to induce second remissions in 30 percent of them. While that response rate is no better than rates achieved by existing chemotherapy--in fact, some studies reported higher rates of remission--the collateral damage to patient health was considerably less with Mylotarg. "It can be given on an outpatient basis in a two-hour intravenous infusion AND has fewer side effects than conventional chemotherapy," said Dr. Richard Larson, director of the leukemia program at the University of Chicago, one of the sites where Mylotarg was tested. Clifford Jonatzke, 52, one of Larson's AML patients, has experienced both. "With regular chemo," he said, "it seemed like the cure was worse than the disease. You're sick all the time. It takes a lot of strength out of you." Jonatzke, who lives in Bridgman, Mich., was hospitalized for four weeks during his first round of chemotherapy in 1996. When his leukemia returned the following year, his only option was a bone marrow transplant. But transplant candidates have to be in remission, AND he couldn't take any more chemo. "So they gave me this experimental drug [Mylotarg]," Jonatzke said. "I only got two doses, AND I went home in between. I didn't get sick at all." The drug made Jonatzke well enough so he could get a transplant of his sister's bone marrow. Three years later, he remains free of cancer. Chemotherapy patients like Jonatzke frequently suffer nausea, vomiting, hair loss, mouth sores, organ damage AND opportunistic infections. That's because chemotherapy agents attack not just cancer cells but other rapidly dividing cells the body needs to function normally, including hair follicles, cells that line the mouth AND stomach, AND those that inhabit the bone marrow. Mylotarg contains a substance called calicheamicin that is toxic to human cells. But because it is piggybacked on an antibody that homes in on leukemia cells, it leaves most normal cells untouched. The antibody targets a protein, called CD33, found on cancerous cells of about 90 percent of patients with AML. The protein is also present in some normal bone marrow cells, Larson said, but not on any normal cell outside the bone marrow. "So blood counts fall, as they do with conventional chemotherapy," he said, "but patients can tolerate it better because there's less injury to other normal tissues." Significantly, the protein is not found in blood stem cells, the seeds from which normal blood AND immune cells originate. So once the leukemia is eradicated, the unscathed stem cells are able to replenish the patients' normal cells, AND their blood counts return to normal. Two "naked" antibodies recently have been approved for the treatment of cancer: Rituxan, for certain blood-cell cancers, AND Herceptin, for a form of breast cancer. Both are synthetic, OR monoclonal, antibodies, large proteins engineered to attach themselves to specific molecules. Monoclonals were touted as a magic bullet in the 1980s, when researchers believed they would eradicate cancer cells simply by latching onto them. Cancer proved to be a more sophisticated AND insidious enemy, AND the promise of monoclonals has not yet panned out. But in recent years researchers have identified better targets AND are learning how to prevent patients from fighting off the antibodies. Several other naked monoclonals are in clinical trials, along with a number of agents, like Mylotarg, in which an antibody is chemically linked to a cell-killing drug OR radioactive isotope. Two such combination drugs could be approved for the treatment of non-Hodgkin's lymphoma in the next year OR so: Coulter Pharmaceutical's Bexxar, which delivers radioactive iodine, AND IDEC Pharmaceuticals' Zevalin, which carries a tiny packet of radioactive yttrium. A third, HuM195-Bi-213, which uses radioactive bismuth, is about to enter the second phase of clinical trials in patients with myeloid leukemia. It is being developed by Dr. David Scheinberg at Memorial Sloan-Kettering Cancer Center in New York. Other antibody-based experimental drugs ferry plant toxins. One, called B43-PAP (for pokeweed antiviral protein), appears promising in treating leukemia in children who have stopped responding to conventional therapies. B43-PAP is being developed at the Parker Hughes Cancer Center outside Minneapolis for children with acute lymphocytic leukemia--the most common pediatric cancer--who have failed standard treatments. "Children in second OR third relapse, especially if they've relapsed after a bone marrow transplant--these children have no hope," said Dr. Fatih Uckun, director of the center. "Now we can put them into remission, AND we can maintain them in remission." Nine of 19 patients in a preliminary study responded to the experimental drug, Uckun said. The remissions were short-lived when B43-PAP was given by itself. But when the drug is added to a "cocktail" of three standard chemotherapy drugs, the responses are much more durable. In an ongoing trial that began last September, Uckun said, 11 of 12 patients achieved complete remissions AND only one of the 11 has relapsed. Some of the most advanced research in this area is being conducted at the National Cancer Institute, where Dr. Ira Pastan heads the molecular biology lab. Two drugs developed in his lab, LMB-2 AND BL22, are showing dramatic results in patients with hairy cell leukemia. The early successes of such drugs, he said, "prove the principle that targeted therapy with toxic substances is possible--something the cancer community would not have accepted a few years ago." It usually takes years for a new drug to be approved for sale. But now experimental cancer drugs like these can sometimes receive fast-track review by the FDA. Mylotarg was OKd under a procedure known as accelerated approval, which was created under pressure from AIDS advocates. It allows drugs to be marketed after an initial showing that they are safe AND provide some benefit but without the randomized trials required to prove they are truly effective. "Accelerated approval applies where there's a clear medical need AND there's no existing treatment of proven benefit," said Dr. Richard Schilsky, associate dean for clinical research at the University of Chicago AND chairman of the FDA advisory committee that reviewed Mylotarg. Under that program, the FDA can grant approval on the basis of data from relatively small trials while larger, randomized trials are going on. If the bigger studies don't confirm the promise shown by the earlier ones, the agency can withdraw its approval OR require the manufacturer to change its labeling. Other cancer drugs have won accelerated FDA approval since 1992, along with new agents for treating AIDS AND HIV, the virus that causes it. Schilsky's committee at first did not recommend approval of Mylotarg. "Even though the toxicity was lower [with Mylotarg], the remission rate was at the low end of what you'd expect from conventional chemotherapy," he said. But the panel eventually recommended approval for relapsed AML patients 60 OR older (as most of them are). Older patients typically have more trouble tolerating chemotherapy, Schilsky said. The approval granted Thursday is even more restrictive. The FDA said the drug is intended only for patients who are not considered good candidates for chemotherapy--although once a drug is approved for one condition, doctors can prescribe it for others. AML is the most common form of acute leukemia in adults. Left untreated, it is usually fatal in two to three months. Even with treatment, most patients die within two years, AND only 15 percent are alive after five years. Researchers emphasize that Mylotarg is not a cure for AML. "It's been shown to put people with leukemia into remission," said Dr. Stephen Nimer of Sloan-Kettering. "But if you don't give them something else, the leukemia comes back." It's still unclear whether Mylotarg's remissions are any more durable than those induced by other drugs OR combinations. AND it's not known whether patients will develop resistance to it as they do to other chemotherapy agents. Dr. Judith Karp, a cancer researcher at the University of Maryland who took part in the clinical trials of Mylotarg, predicted that it will ultimately be given in combination with other therapies. Nevertheless, Karp said, "I think it's an exciting step forward in treating acute leukemia." ******************************************************************************************* יש כמובן דברים נוספים בתחום האלטרנטיבי שכדאי מאוד לשלב. לדוגמא לפרוטוקול Kelly יש הצלחה מסוימת מוגבלת עם AML. גם לתזונת ג'והנה באדוויג יש הצלחות עם לויקמיה, אם כי אני לא בטוח לגבי AML. בברכה, גובי www.cure-cancer-naturally.com