Citations

Circulating cytokines, hormones, and growth factors control all aspects of cell proliferation, differentiation, angiogenesis, apoptosis, and senescence. These chemical signals are propagated from the cell surface to intracellular processes via sequential kinase signaling, arranged in modules that exhibit redundancy and cross talk. This signal transduction system comprising growth factors, transmembrane receptor proteins, and cytoplasmic secondary messengers is often exploited to optimize tumor growth and metastasis in malignancies. Thus, it represents an attractive target for cancer therapy. This review will summarize current knowledge of selected intracellular signaling networks and their role in cancer therapy. The focus will be on pathways for which inhibitory agents are currently undergoing clinical testing. Original data for inclusion in this review were identified through a MEDLINE search of the literature. All papers from 1966 through March 2005 were identified by the following search terms: “signal transduction,” “intracellular signaling,” “kinases,” “proliferation,” “growth factors,” and “cancer therapy.” All original research and review papers related to the role of intracellular signaling in oncogenesis and therapeutic interventions relating to abnormal cell signaling were identified. This search was supplemented by a manual search of the Proceedings of the Annual Meetings of the American Association for Cancer Research, American Society of Clinical Oncology, and the American Association for Cancer Research (AARC) –European Organisation for Research and Treatment of Cancer (EORTC) –National Cancer Institute (NCI) Symposium on New Anticancer Drugs.

Purpose We determined the maximum-tolerated dose (MTD) and the dose-limiting toxicities (DLT) of 17-allylamino-17-demethoxygeldanamycin (17-AAG) when infused on days 1, 8, and 15 of a 28-day cycle in advanced solid tumor patients. We also characterized the pharmacokinetics of 17-AAG, its effect on chaperone and client proteins, and whether cytochrome P450 (CYP) 3A5 and NAD(P)H:quinone oxidoreductase 1 (NQO1) polymorphisms affected 17-AAG disposition or toxicity. Patients and Methods An accelerated titration design was used. Biomarkers were measured in peripheral-blood mononuclear cells (PBMCs) at baseline and on days 1 and 15, and pharmacokinetic analysis was performed on day 1 of cycle 1. CYP3A5*3 and NQO1*2 genotypes were determined and correlated with pharmacokinetics and toxicity. Results Twenty-one patients received 52 courses at 11 dose levels. DLTs at 431 mg/m2 were grade 3 bilirubin (n = 1), AST (n = 1), anemia (n = 1), nausea (n = 1), vomiting (n = 1), and myalgias (n = 1). No tumor responses were seen. 17-AAG consistently increased heat shock protein (Hsp) 70 levels in PBMCs. At the MTD, the clearance and half-life (t1/2) of 17-AAG were 11.6 L/h/m2 and 4.15 hours, respectively; whereas the active metabolite 17-aminogeldanamycin had a t1/2 of 7.63 hours. The CYP3A5*3 and NQO1*2 polymorphisms were not associated with 17-AAG toxicity. The CYP3A5*3 polymorphism was associated with higher 17-AAG clearance. Conclusion The MTD of weekly 17-AAG is 308 mg/m2. 17-AAG induced Hsp70 in PBMCs, indicating that Hsp90 has been affected. Further evaluation of 17-AAG is ongoing using a twice-weekly regimen, and this schedule of 17-AAG is being tested in combination with chemotherapy.

Purpose To describe the prevalence, clinical characteristics, and pattern of use of complementary and alternative medicine (CAM) in patients enrolled onto phase I trials. Patients and Methods Questionnaires were administered to 108 patients with advanced malignancies enrolled onto phase I chemotherapy trials at the Mayo Clinic Comprehensive Cancer Center (Rochester, MN). CAM was classified into two modalities, pharmacologic and nonpharmacologic. Clinical and demographic data, including age, sex, and prior cancer treatment, were subsequently obtained from patient charts and examined for any correlation with CAM use, using χ2 analysis. Results One hundred two survey forms were returned. Among respondents, 88.2% (90 of 102) had used at least one CAM modality; 93.3% (84 of 90) and 53.3% (48 of 90) had used pharmacologic and nonpharmacologic CAM, respectively; and 46.7% (42 of 90) used both modalities. Vitamin and mineral preparations constituted 89.3% (75 of 84) of all pharmacologic CAM used. Intake was highest for vitamins E (48.8% [41 of 84]) and C (38.1% [32 of 84]), and 71.4% (60 of 84) of respondents took nonvitamin/mineral agents. Green tea (29.8% [25 of 84]), echinacea (13.1% [11 of 84]), and essiac (9.5% [8 of 84]) were the most popular. Prayer and spiritual practices were the most commonly used nonpharmacologic CAM, accounting for 52.1% (25 of 48). Chiropractors, the most frequently visited nontraditional medicine practitioners, were consulted by only 10% (9 of 90) of those who practiced CAM. Both CAM modalities were used more frequently by women (53.5% [23 of 43]) than men (40.4% [19 of 47]). Conclusion CAM use is common among patients in phase I trials and should be ascertained by investigators, because some of the agents used may interact with investigational agents and affect adverse effects and/or efficacy.

Purpose This multicenter, open-label, phase II study was undertaken to assess the antitumor activity and safety of the oral mitogen-activated extracellular signal regulated kinase kinase (MEK) inhibitor, CI-1040, in breast cancer, colon cancer, non-small-cell lung cancer (NSCLC), and pancreatic cancer. Patients and Methods Patients with advanced colorectal, NSCLC, breast, or pancreatic cancer received oral CI-1040 continuously at 800 mg bid. All patients had measurable disease at baseline, a performance status of 2 or less, and adequate bone marrow, liver, and renal function. Expression of pERK, pAkt, and Ki-67 was assessed in archived tumor specimens by quantitative immunohistochemistry. Results Sixty-seven patients with breast (n = 14), colon (n = 20), NSCLC (n = 18), and pancreatic (n = 15) cancer received a total of 194 courses of treatment (median, 2.0 courses; range, one to 14 courses). No complete or partial responses were observed. Stable disease (SD) lasting a median of 4.4 months (range, 4 to 18 months) was confirmed in eight patients (one breast, two colon, two pancreas, and three NSCLC patients). Treatment was well tolerated, with 81% of patients experiencing toxicities of grade 2 or less severity. Most common toxicities included diarrhea, nausea, asthenia, and rash. A mild association (P < .055) between baseline pERK expression in archived tumor specimens and SD was observed. Conclusion CI-1040 was generally well tolerated but demonstrated insufficient antitumor activity to warrant further development in the four tumors tested. PD 0325901, a second generation MEK inhibitor, has recently entered clinical development and, with significantly improved pharmacologic and pharmaceutical properties compared with CI-1040, it may better test the therapeutic potential of MEK inhibition in cancer.

Abstract Rarely, myelodysplastic syndrome (MDS) is complicated by an acquired form of α-thalassemia (α-thalassemia in myelodysplastic syndrome [ATMDS]) characterized by hypochromic, microcytic, anisopoikilocytic red blood cells with hemoglobin H (HbH) inclusions. Acquired mutations in ATRX, a chromatin remodeling gene, have recently been found in 12 patients with typical features of ATMDS, though they have not been detected in MDS patients with similar red blood cell findings but little HbH. The α-globin genes themselves have appeared normal in all ATMDS patients studied to date. Here we characterize the molecular defect in a unique MDS patient with rare HbH inclusions in which an abnormal clone lost a greater than 1.9-Mb segment of the telomeric region of the short arm of one allele of chromosome 16, including both α-globin genes. Red blood cell changes associated with this acquired somatic genotype (––/αα) are surprisingly severe, demonstrating that a minor globin chain imbalance may be unexpectedly deleterious during the abnormal erythropoiesis that occurs in the context of MDS.

Purpose: We sought to determine the maximum-tolerated dose (MTD) and evaluate the toxicities and clinical activity of two irinotecan (CPT-11), fluorouracil (FU), leucovorin (LV), and oxaliplatin schedules in patients with advanced solid tumors. Additionally, we investigated the effect of CPT-11 on oxaliplatin pharmacokinetics. Patients and Methods: Thirteen patients (cohort 1) received intravenous CPT-11 (infusion) and FU/LV (bolus) on days 1, 8, 15, and 22 and oxaliplatin (infusion) on days 1 and 15 every 6 weeks for a total 37 courses (median, three courses) at three dose levels. Twenty-two cohort 2 patients received intravenous CPT-11/oxaliplatin (infusion, day 1) and FU/LV (90-minute bolus infusion, days 2 to 5) every 3 weeks for a total of 122 courses (median, four courses) at three dose levels. Pharmacokinetic and neurotoxicity assessments were performed at the cohort 2 MTD. Results: Dose-limiting toxicity (DLT) seen in both cohorts at the starting dose required dose de-escalation. Cohort 1 DLT included diarrhea and neutropenia. In cohort 2, diarrhea, vomiting, dehydration, neutropenia, febrile neutropenia, and paresthesias were DLTs. Antitumor activity was seen in both cohorts. In cohort 2, the total platinum area under the curve of patients increased 17% in cycle 2 (P = .048), but objective neurotoxicity was not seen. Conclusion: The toxicities resulting from the addition of oxaliplatin to CPT-11/FU/LV are significant but manageable. The MTDs for the weekly schedule are CPT-11 (75 mg/m2), oxaliplatin (50 mg/m2), FU (320 mg/m2), and LV (20 mg/m2); and, for the 3-weekly schedule, the MTDs are CPT-11 (175 mg/m2), oxaliplatin (85 mg/m2), FU (240 mg/m2), and LV (20 mg/m2). Second-cycle platinum accumulation raises the possibility for enhanced cumulative neurotoxicity with CPT-11/oxaliplatin combinations.

Abstract Adaphostin (NSC 680410), an analog of the tyrphostin AG957, was previously shown to induce Bcr/abl down-regulation followed by loss of clonogenic survival in chronic myelogenous leukemia (CML) cell lines and clinical samples. Adaphostin demonstrated selectivity for CML myeloid progenitors in vitro and remained active in K562 cells selected for imatinib mesylate resistance. In the present study, the mechanism of action of adaphostin was investigated in greater detail in vitro. Initial studies demonstrated that adaphostin induced apoptosis in a variety of Bcr/abl- cells, including acute myelogenous leukemia (AML) blasts and cell lines as well as chronic lymphocytic leukemia (CLL) samples. Further study demonstrated that adaphostin caused intracellular peroxide production followed by DNA strand breaks and, in cells containing wild-type p53, a typical DNA damage response consisting of p53 phosphorylation and up-regulation. Importantly, the antioxidant N-acetylcysteine (NAC) blunted these events, whereas glutathione depletion with buthionine sulfoximine (BSO) augmented them. Collectively, these results not only outline a mechanism by which adaphostin can damage both myeloid and lymphoid leukemia cells, but also indicate that this novel agent might have a broader spectrum of activity than originally envisioned. (Blood. 2003;102:4512-4519)