To enhance therapeutic efficacy and reduce adverse effects, practitioners of traditional Chinese medicine (TCM) prescribe a combination of plant species/minerals, called formulae, based on clinical experience. Nearly 100,000 formulae have been recorded, but the working mechanisms of most remain unknown. In trying to address the possible beneficial effects of formulae with current biomedical approaches, we use Realgar-Indigo naturalis formula (RIF), which has been proven to be very effective in treating human acute promyelocytic leukemia (APL) as a model. The main components of RIF are realgar, Indigo naturalis, and Salvia miltiorrhiza, with tetraarsenic tetrasulfide (A), indirubin (I), and tanshinone IIA (T) as major active ingredients, respectively. Here, we report that the ATI combination yields synergy in the treatment of a murine APL model in vivo and in the induction of APL cell differentiation in vitro. ATI causes intensified ubiquitination/degradation of promyelocytic leukemia (PML)-retinoic acid receptor ␣ (RAR␣) oncoprotein, stronger reprogramming of myeloid differentiation regulators, and enhanced G1/G0 arrest in APL cells through hitting multiple targets compared with the effects of mono-or biagents. Furthermore, ATI intensifies the expression of Aquaglyceroporin 9 and facilitates the transportation of A into APL cells, which in turn enhances A-mediated PML-RAR␣ degradation and therapeutic efficacy. Our data also indicate A as the principal component of the formula, whereas T and I serve as adjuvant ingredients. We therefore suggest that dissecting the mode of action of clinically effective formulae at the molecular, cellular, and organism levels may be a good strategy in exploring the value of traditional medicine.traditional chinese medicine ͉ active ingredient ͉ tetraarsenic tetrasulfide ͉ synergism ͉ systems biology T he complexity of medicine suggests that treatment protocols should be carefully designed, and the construction of a prescription is an art in fighting disease. Increasing evidence demonstrates that, in treating illnesses, including cancer (1) and HIV/AIDS (2), treatment regimens containing multiple drugs with distinct but related mechanisms can usually amplify the therapeutic efficacies of each agent, leading to maximal therapeutic efficacy with minimal adverse effects. Interestingly, combination therapy has been advocated for Ͼ2,500 years by prescriptions called formulae (3, 4) in traditional Chinese medicine (TCM), a unique medical system assisting the ancient Chinese in dealing with disease. Typically, formulae consist of several types of medicinal herbs or minerals, in which one represents the principal component, and others serve as adjuvant ones to assist the effects or facilitate the delivery of the principal component (3, 4). It is believed that, at least in some formulae, multiple components could hit multiple targets and exert synergistic therapeutic efficacies (3, 4). However, essential compounds have not been identified in most formulae, whereas precise mechanisms of form...

Bosutinib, a dual Src/Abl kinase inhibitor, has shown potent activity against chronic myeloid leukemia (CML). In this phase 1/2 study we evaluated bosutinib in patients with chronic phase imatinib-resistant or imatinib-intolerant CML. Part 1 was a dose-escalation study to determine the recommended starting dose for part 2; part 2 evaluated the efficacy and safety of bosutinib 500 mg once-daily dosing. The study enrolled 288 patients with imatinib-resistant (n ‫؍‬ 200) or imatinibintolerant (n ‫؍‬ 88) CML and no other previous kinase inhibitor exposure. At 24 weeks, 31% of patients achieved major cytogenetic response (primary end point). After a median follow-up of 24.2 months, 86% of patients achieved complete hematologic remission, 53% had a major cytogenetic response (41% had a complete cytogenetic response), and 64% of those achieving complete cytogenetic response had a major molecular response. At 2 years, progression-free survival was 79%; overall survival at 2 years was 92%.

All-trans retinoic acid (ATRA)/arsenic trioxide (ATO) combinationbased therapy has benefitted newly diagnosed acute promyelocytic leukemia (APL) in short-term studies, but the long-term efficacy and safety remained unclear. From April 2001, we have followed 85 patients administrated ATRA/ATO with a median follow-up of 70 months. Eighty patients (94.1%) entered complete remission (CR). Kaplan-Meier estimates of the 5-year event-free survival (EFS) and overall survival (OS) for all patients were 89.2% ؎ 3.4% and 91.7% ؎ 3.0%, respectively, and the 5-year relapse-free survival (RFS) and OS for patients who achieved CR (n ‫؍‬ 80) were 94.8% ؎ 2.5% and 97.4% ؎ 1.8%, respectively. Upon ATRA/ATO, prognosis was not influenced by initial white blood cell count, distinct PML-RAR␣ types, or FLT3 mutations. The toxicity profile was mild and reversible. No secondary carcinoma was observed, and 24 months after the last dose of ATRA/ATO, patients had urine arsenic concentrations well below the safety limit. These results demonstrate the high efficacy and minimal toxicity of ATRA/ATO treatment for newly diagnosed APL in long-term follow-up, suggesting a potential frontline therapy for de novo APL.combination therapy ͉ 5-year EFS ͉ 5-year OS ͉ residual disease ͉ arsenic retention A cute promyelocytic leukemia (APL) is the M3 subtype of acute myeloid leukemia (AML) and is characterized by an accumulation of abnormal promyelocytes in the bone marrow and a severe bleeding tendency. Additionally, in the great majority of cases, APL is associated with the t(15,17) chromosomal translocation and resultant PML-RAR␣ transcripts that encode the leukemogenic PML-RAR␣ fusion protein (1). Five decades ago, APL was the most fatal type of acute leukemia and was considered essentially untreatable (2). The first breakthrough came with the use of anthracyclines, which improved the complete remission (CR) rate but provided a low 5-year overall survival (OS) (3). The introduction of all-trans retinoic acid (ATRA) therapy resulted in terminal differentiation of APL cells and a 90-95% CR rate in patients (1, 4), and subsequent combination of ATRA with chemotherapy raised the 5-year disease-free survival (DFS) rate up to 74% (5). In the 1990s, significant benefits of arsenic trioxide (ATO) were reported, which further improved the outcome of patients with APL (6, 7). ATO exerts dose-dependent dual effects on APL cells, with low concentrations inducing partial differentiation and relatively high concentrations triggering apoptosis. Of note, both ATRA and ATO induce catabolism of the PML-RAR␣ fusion protein, demonstrating a paradigm for rationally targeted therapy in leukemia. However, between 20% and 30% of newly diagnosed APL patients treated with regimens based on the use of ATRA or ATO as single agents will develop disease recurrence or drug resistance.To improve further the clinical outcome of APL, therapeutic strategies should be designed to include combinatorial use of drugs with distinct but convergent mechanisms that may amplify treatment effic...