A phase 1 dose-escalation study of ARRY-520, a kinesin spindle protein inhibitor, in patients with advanced myeloid leukemias.

BACKGROUND: ARRY-520 selectively inhibits the mitotic kinesin spindle protein (KSP), which leads to abnormal monopolar spindle formation and apoptosis. METHODS: A phase 1 trial was conducted to establish the safety and the maximum tolerated dose (MTD) of ARRY-520 given as a 1-hour infusion in either a single dose or on a day 1, 3, and 5 divided-dose schedule per cycle in patients with advanced or refractory myeloid leukemias. Additional objectives were to characterize pharmacokinetics, assess preliminary clinical activity, and explore biomarkers of KSP inhibition with ARRY-520. A total of 36 patients with acute myelogenous leukemia (n = 34) or myelodysplastic syndromes (n = 2) with a median age of 66 years (range, 21-88 years) were enrolled: 15 in the single-dose schedule (dose levels: 2.5, 3.75, 4.5, and 5.6 mg/m(2)) and 21 in the divided-dose schedule (dose levels: 0.8, 1.2, 1.5, and 1.8 mg/m(2)/day). RESULTS: The MTD was 4.5 mg/m(2) total dose per cycle for both dose schedules. Dose-limiting toxicities included mucositis, exfoliative rash, hand-foot syndrome, and hyperbilirubinemia. Grades 3 or 4 reversible drug-related myelosuppression were observed in 33 of 36 patients. Plasma pharmacokinetic analyses revealed low clearance of ARRY-520 (~3 L/hour), a volume of distribution of ~450 L, and a median terminal half-life of >90 hours. Monopolar spindles were observed in blood mononuclear cells, through use of 4',6-diamidino-2-phenylindole nucleic acid stain and antitubulin antibodies. CONCLUSIONS: On the basis of the relative lack of clinical activity, further development of ARRY-520 as an antileukemic agent was halted. (Clinicaltrials.gov identifier NCT00637052).

Things We Do For No Reason: Neutropenic Diet.

For several decades, providers have routinely restricted the diets of neutropenic cancer patients by eliminating foods that might harbor pathogenic microbes to reduce infection rates. These diets, known as neutropenic or low-bacteria diets, are prescribed across the country with little uniformity in the extent or content of prescription. These diets are difficult to follow and force patients to omit fresh fruits and vegetables and limit dairy and meat products from their diet. These dietary omissions compromise nutritional intake in patients who are already at high risk of malnutrition. Randomized trials have shown that these restrictive diets are not superior in preventing infections than more liberalized diets. Evidence shows that adherence to the Safe Food-Handling guidelines issued by the Food and Drug Administration, a mandate for all hospital kitchens, provides adequate protection against food-borne infection, precluding the need for the neutropenic diet. Thus, routine use of the neutropenic diet should be abandoned.

Antileukemic activity of genistein, a major isoflavone present in soy products.

Soy has been used in traditional medicine for the treatment of various diseases, including cancer. The isoflavones present in soy have been shown in animal models to have cancer-preventing activity. However, the therapeutic effects of isoflavones against cancer are still unclear. We have evaluated the in vitro and in vivo antileukemic activity of genistein (1), a major isoflavone present in soy. We observed that it produced a dose- and time-dependent antineoplastic activity against myeloid and lymphoid leukemic cell lines. In addition, genistein treatment of the leukemic cells reactivated tumor suppressor genes that were silenced by aberrant DNA methylation. A genistein-enriched diet produced a moderate, but significant, antileukemic effect in mice. The limited extent of this in vivo response may have been due to the rapid metabolic inactivation of genistein in mice. Due to the longer half-life of genistein in humans, a soy-enriched diet has the potential to produce plasma levels of this isoflavone in the range of the concentrations used in vitro that produced an antileukemic activity.

Omega-3 fatty acid-containing liposomes in cancer therapy.

omega-3 fatty acids are associated with reduced growth and incidence of certain cancers, and in this report we demonstrate that a fish oil diet (rich in omega-3 fatty acids) enhances the longevity of mice bearing the myeloid leukemia T27A. We have proposed that the omega-3 fatty acid docosahexaenoic acid (DHA, 22:6 delta 4,7,10,13,16,19) may induce structural changes in tumor cell plasma membranes resulting in reduced tumor growth in vitro. Here, we test whether liposomes containing DHA (18:0, 22:6 PC) have antitumor effects in vivo, leading to enhanced longevity of the tumor-bearing host. Male BALB/c mice (6-8 weeks old) were inoculated intraperitoneally with a T27A tumor dose known to cause 100% mortality of syngeneic (BALB/c) mice in less than 2 weeks. Small unilamellar vesicles (liposomes) were prepared, composed of phosphatidylcholine (PC) with 18:0 in the sn-l position and one of the following fatty acids in the sn-2 position: 18:0, 18:1 omega 9 (oleic), 18:3 omega 3 (alpha-linolenic), 20:4 omega 6 (arachidonic), 22:6 omega 3 (docosahexaenoic). The liposomes were injected intraperitoneally into tumor-bearing mice at various times: concurrently with the tumor inoculum, at select times during tumor growth, and when the mice were moribund. Mouse survival was then charted. DHA-containing lipid vesicles (18:0, 22:6 PC) caused a statistically significant increase in survival of the tumor-bearing mice when compared with 18:0, 18:1 PC. Lipid vesicles of 18:0, 18:0 PC showed no benefit, and 18:0, 20:4 PC was not significantly different than 18:0, 18:1 PC. Lipid vesicles containing a different omega-3 fatty acid, 18:0, 18:3 PC, also effectively enhanced tumor-bearing mouse survival. The greatest benefit was achieved if either the liposome treatments were spaced throughout the tumor growth period, or if the tumor inoculum was suspended in the liposome preparation (without further liposome treatments). Neither lipid peroxidation nor prolonged inflammatory responses appeared to be pertinent, leaving membrane structural changes as a feasible mode of liposome action. With antitumor properties of their own, omega-3 fatty acid-containing lipid vesicles may offer an important new avenue in combination cancer therapies.