Continued Treatment Effect of Zoledronic Acid Dosing Every 12 vs 4 Weeks in Women With Breast Cancer Metastatic to Bone: The OPTIMIZE-2 Randomized Clinical Trial.

Importance: Zoledronic acid, a potent bisphosphonate, is commonly administered to patients with bone metastases to reduce the risk of skeletal-related events (SREs). However, there have been concerns regarding its long-term monthly administration.

Objective: To examine whether zoledronic acid every 12 weeks was noninferior to zoledronic acid every 4 weeks in patients with metastatic breast cancer that involved the bone who had previously received a standard dosing regimen of zoledronic acid and/or pamidronate disodium.

Investigation of alkyne regioselectivity in the ni-catalyzed benzannulation of cyclobutenones.

A Ni-catalyzed benzannulation reaction of cyclobutenones and alkynes provides a rapid synthesis of heavily substituted phenols. The regioselectivity of this reaction can be modulated by variation of substituents on the alkyne. Though the incorporation of Lewis basic donors provides modest selectivities, the use of aryl substituents can provide high levels of regiocontrol.

Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma.

Purpose: A multicenter, randomized phase II trial, RECORD-3, was conducted to compare first-line everolimus followed by sunitinib at progression with the standard sequence of first-line sunitinib followed by everolimus in patients with metastatic renal cell carcinoma.

Patients And Methods: RECORD-3 used a crossover treatment design. The primary objective was to assess progression-free survival (PFS) noninferiority of first-line everolimus compared with first-line sunitinib.

Si-free enolate Claisen rearrangements of enamido substrates.

α-Alkyl β-amino esters are available in high diastereoselectivity through a silicon-free Claisen enolate [3,3]-sigmatropic rearrangement of enamide esters. Optimisation studies have probed the crucial role of the initial enolisation and the nature of the enamide N-centre. The demonstration of chirality transfer and the formation of β-proline systems, is also presented.

Phase III trial of cetuximab, bevacizumab, and 5-fluorouracil/leucovorin vs. FOLFOX-bevacizumab in colorectal cancer.

Background: Cetuximab (C), alone or with irinotecan, demonstrates activity in irinotecan-refractory colorectal cancer (CRC). Activity of 5-fluorouracil (5-FU), leucovorin (L), and bevacizumab (B), and preliminary data of cetuximab + bevacizumab, and toxicity profiles suggests that FOLF-CB (5-FU, L, C+B) may have activity with a favorable toxicity profile as first-line therapy.

Methods: Eligible patients were randomized at registration to either arm A (mFOLFOX6-B) (modified, 5-FU.

Final 5-year results of Z-FAST trial: adjuvant zoledronic acid maintains bone mass in postmenopausal breast cancer patients receiving letrozole.

Background: Postmenopausal breast cancer (BC) patients receiving adjuvant aromatase inhibitor therapy are at risk of progressive bone loss and fractures. Zoledronic acid inhibits osteoclastic bone resorption, is effective in maintaining bone health, and may therefore be beneficial in this setting.

Methods: Overall, 602 postmenopausal women with early, hormone receptor-positive BC receiving adjuvant letrozole were randomized (301 each group) to receive upfront or delayed-start zoledronic acid (4 mg intravenously every 6 months) for 5 years.

A practical protocol for the highly E-selective formation of aryl-substituted silylketene acetals.

The E/Z-selectivity in the formation of silylketene acetals derived from phenylacetate esters, mediated by LiHMDS, has been studied by in situ NMR techniques. The formation is seen to be highly E-selective with use of the newly developed protocol. Isolated aryl-substituted silylketene acetals are now attainable with high levels of E-geometrical purity in excellent yield.

Zoledronic acid inhibits adjuvant letrozole-induced bone loss in postmenopausal women with early breast cancer.

Purpose: Treatment with aromatase inhibitors decreases bone mineral density (BMD) and may increase the risk of fractures in postmenopausal women with early-stage breast cancer. The addition of zoledronic acid to adjuvant letrozole therapy may protect against bone loss.

Patients And Methods: Patients receiving adjuvant letrozole were randomly assigned to receive either upfront or delayed-start zoledronic acid (4 mg intravenously every 6 months).

Detailed analysis of a randomized phase III trial: can the tolerability of capecitabine plus docetaxel be improved without compromising its survival advantage?

Background: In a phase III trial, 3-weekly capecitabine (1250 mg/m(2) twice daily days 1-14) plus docetaxel (75 mg/m(2) day 1) demonstrated significantly superior overall survival to 3-weekly docetaxel (100 mg/m(2) day 1). We report a retrospective analysis of the impact of capecitabine/docetaxel dose reduction on safety and efficacy.

Patients And Methods: Safety and efficacy data were analyzed retrospectively according to the actual doses of capecitabine and docetaxel administered.

Multicenter Phase II study of estramustine phosphate plus weekly paclitaxel in patients with androgen-independent prostate carcinoma.

Background: The current study determined the efficacy and toxicity of weekly paclitaxel in combination with estramustine phosphate (EMP) in patients with androgen-independent prostate carcinoma (AIPC).

Methods: Patients with progressive AIPC received 90 mg/m2 paclitaxel by 1-hour intravenous infusion weekly for 3 weeks, followed by a 1-week treatment rest. Patients received 140 mg EMP orally 3 times daily on the day before, the day of, and the day after paclitaxel administration.

A comparison of independent living outcomes following traumatic brain injury and spinal cord injury.

This study compares independent living outcomes in persons with traumatic brain injury (TBI) and spinal cord injury (SCI). Both injuries represent life-altering events that are known to have a negative impact on independent living and are predominantly experienced by members of the same demographic group. However, the types of resultant impairments and disabilities experienced by the two populations differ substantially.

Differential immunohistochemical staining for DNA topoisomerase II alpha and beta in human tissues and for DNA topoisomerase II beta in non-Hodgkin's lymphomas.

Topoisomerase II (Topo II) is the target for several chemotherapeutic agents, including doxorubicin and etoposide, termed Topo II poisons. Previous studies from cancer cell lines and clinical specimens attempted to correlate expression of Topo II with drug sensitivity. Mammalian cells, however, contain two isoforms of Topo II, termed Topo II alpha (subunit molecular weight, 170 kDa) and Topo II beta (subunit molecular weight, 180 kDa), both of which are sensitive to Topo II poisons.

Selective use of an alternative stop codon and polyadenylation signal within intron sequences leads to a truncated topoisomerase II alpha messenger RNA and protein in human HL-60 leukemia cells selected for resistance to mitoxantrone.

Topoisomerase II alpha is an essential nuclear enzyme involved in DNA replication and a target for many of the clinically useful antineoplastic agents. In a mitoxantrone-selected human leukemia cell line, HL-60/MX2, cellular topoisomerase II (topo II) catalytic activity is decreased, in association with the finding of reduced nuclear topo II alpha and beta protein levels. In addition, HL-60/MX2 cells contain a novel M(r) 160,000 topo II alpha-related protein that localizes predominantly to the cell cytoplasm (W.

Adjusting the dose of intravenous ondansetron plus dexamethasone to the emetogenic potential of the chemotherapy regimen.

Purpose: This pilot, open-label study evaluates the antiemetic efficacy and safety of a single 20-mg intravenous (IV) dose of dexamethasone combined with a single IV dose of ondansetron (32, 24, or 8 mg) in patients receiving highly emetogenic (HE), moderately high emetogenic (MHE), or moderately emetogenic (ME) chemotherapy, respectively.

Patients And Methods: One hundred forty-six patients received a single 20-mg IV dose of dexamethasone over 15 minutes beginning 45 minutes before chemotherapy and either a single 32-, 24-, or 8-mg IV dose of ondansetron over 15 minutes beginning 30 minutes before chemotherapy. Patients were evaluated for emetic episodes, extent of nausea, and adverse events for 24 hours after chemotherapy.

Alterations in the topoisomerase II alpha gene, messenger RNA, and subcellular protein distribution as well as reduced expression of the DNA topoisomerase II beta enzyme in a mitoxantrone-resistant HL-60 human leukemia cell line.

A human HL-60 leukemia cell line selected for resistance to mitoxantrone, HL-60/MX2, displays cross-resistance only to agents whose cytotoxicities result from interaction with the nuclear enzyme DNA topoisomerase II (topo II). The topo II catalytic activity is reduced 2-fold in the drug-resistant cell line in association with the absence of the M(r) 180,000 isoform of topo II and the finding of novel M(r) 160,000 topo II alpha-related immunoreactive protein in these cells by immunoblot. The topo II alpha (M(r) 170,000) protein levels in nuclear extracts from the HL-60/MX2 cells were noted on average to be approximately 40% lower than in comparable HL-60 nuclei.

Mutation at the catalytic site of topoisomerase I in CEM/C2, a human leukemia cell line resistant to camptothecin.

We developed previously a resistant cell line, CEM/C2, from the human leukemia cell line CCRF-CEM by stepwise selection in camptothecin. This cell line is 974-fold more resistant to camptothecin than parental cells. Resistance is only partially explained by 2-fold reductions in topoisomerase I protein and mRNA levels.

Altered topoisomerase I expression in two subclones of human CEM leukemia selected for resistance to camptothecin.

Two camptothecin-resistant variants of the CEM human leukemia cell line were developed by stepwise selection in camptothecin (CPT) in vitro. The two lines, named CEM/C1 and CEM/C2, were found to be approximately 31- and 970-fold less sensitive to CPT, respectively, than the CEM parental line and variably cross-resistant to the CPT analogs 9-amino-CPT, 10,11-methylenedioxy-CPT, and topotecan. Levels of DNA-protein complex formation resulting from cell exposure to CPT were found to be progressively reduced in the CPT-resistant cells, despite equivalent CPT accumulation in the drug-sensitive and -resistant cells.

A randomized, double-blind comparison of intravenous ondansetron alone and in combination with intravenous dexamethasone in the prevention of high-dose cisplatin-induced emesis.

Purpose: This study compares the efficacy and safety of ondansetron alone with that of ondansetron plus dexamethasone in the prevention of emesis induced by high-dose cisplatin (> or = 100 mg/m2).

Patients And Methods: This multicenter study used a randomized, double-blind, parallel-group design. Chemotherapy-naive patients were randomized to receive intravenous (IV) ondansetron (Zofran, Cerenex Pharmaceuticals, Research Triangle Park, NC) 0.

Peripherally inserted central venous catheters. Low-risk alternatives for ongoing venous access.

We prospectively evaluated the use of peripherally inserted central venous catheters to provide ongoing venous access in general medical and surgical patients in a Department of Veterans Affairs medical center. Between 1985 and 1988 trained nurses successfully inserted 393 catheters in 460 suitable patients (an 85.4% success rate).

Single-strand conformational polymorphism analysis of the M(r) 170,000 isozyme of DNA topoisomerase II in human tumor cells.

Five cell lines selected for resistance to the cytotoxicity of inhibitors of DNA topoisomerase II have point mutations in the gene that codes for the M(r) 170,000 form of this enzyme. In each case, the mutation results in an amino acid change in or near an ATP binding sequence of the M(r) 170,000 isozyme of topoisomerase II. We used single-strand conformational polymorphism analysis to screen for similar mutations in other drug-resistant cell lines or in leukemic cells from patients previously treated with etoposide or teniposide.

Phase II trial of mitotane and cisplatin in patients with adrenal carcinoma: a Southwest Oncology Group study.

Purpose: Previous reports of chemotherapy in patients with adrenal cancer have described responses to cisplatin (CDDP). Because of these reports of good results, a phase II trial that used CDDP with and without mitotane (o,p'DDD) was initiated.

Patients And Methods: Patients with metastatic or residual adrenocortical carcinoma with objectively measurable disease or biochemical abnormalities were divided into good-risk and poor-risk categories.

Isolation, purification, and characterization of two new chemical decomposition products of methylazoxyprocarbazine.

We have previously reported that the antineoplastic agent, procarbazine, in aqueous solutions was chemically oxidized to its azoxy metabolites (methylazoxy and benzylazoxy). To determine if there was additional metabolism of the most active metabolite, methylazoxyprocarbazine, it was incubated in the presence and absence of CCRF-CEM human leukemia cells. Incubations were extracted, and potential metabolites were detected by HPLC with UV detection and by combined HPLC and thermospray mass spectrometric analysis.

Non-enzymatic activation of procarbazine to active cytotoxic species.

The cellular cytotoxicity of procarbazine is thought to result from bioactivation of the parent compound through reactive intermediates to an ultimate alkylating species. Procarbazine is converted initially to azoprocarbazine, which is then N-oxidized through a cytochrome P-450-mediated process to a mixture of the positional isomers, benzylazoxyprocarbazine and methylazoxyprocarbazine. In order to define the bioactivation events that lead to the cytotoxic species, the in vitro cytotoxicities of the purified azoxy isomers as well as of the parent compound, procarbazine, were evaluated with the human leukemia cell line, CCRF-CEM.

Mitoxantrone resistance in HL-60 leukemia cells: reduced nuclear topoisomerase II catalytic activity and drug-induced DNA cleavage in association with reduced expression of the topoisomerase II beta isoform.

Mitoxantrone-resistant variants of the human HL-60 leukemia cell line are cross-resistant to several natural product and synthetic antineoplastic agents. The resistant cells (HL-60/MX2) retain sensitivity to the Vinca alkaloids vincristine and vinblastine, drugs that are typically associated with the classical multidrug resistance phenotype. Mitoxantrone accumulation and retention are equivalent in the sensitive and resistant cell types, suggesting that mitoxantrone resistance in HL-60/MX2 cells might be associated with an alteration in the type II DNA topoisomerases.

Human tumor cell line resistance to chemotherapeutic agents does not predict resistance to natural killer or lymphokine-activated killer cell-mediated cytolysis.

Cancer cells selected for resistance to natural product chemotherapeutic agents typically display cross-resistance to a variety of structurally and mechanistically diverse agents, a phenomenon known as multidrug resistance. Preliminary studies involving cells selected for multidrug resistance in vitro have suggested that the development of resistance to these agents might simultaneously confer resistance to some forms of immunotherapy. Using human tumor cell line models, we have investigated the relationship between either intrinsic or selected multidrug resistance and sensitivity to natural killer (NK) or lymphokine-activated killer (LAK) cell-mediated cytolysis.