The dynamic processivity of individual T4 lysozyme molecules was monitored in the presence of either linear or cross-linked peptidoglycan substrates. Single-molecule monitoring was accomplished using a novel electronic technique in which lysozyme molecules were tethered to single-walled carbon nanotube field-effect transistors through pyrene linker molecules. The substrate-driven hinge-bending motions of lysozyme induced dynamic electronic signals in the underlying transistor, allowing long-term monitoring of the same molecule without the limitations of optical quenching or bleaching. For both substrates, lysozyme exhibited processive low turnover rates of 20-50 s(-1) and rapid (200-400 s(-1)) nonproductive motions. The latter nonproductive binding events occupied 43% of the enzyme's time in the presence of the cross-linked peptidoglycan but only 7% with the linear substrate. Furthermore, lysozyme catalyzed the hydrolysis of glycosidic bonds to the end of the linear substrate but appeared to sidestep the peptide cross-links to zigzag through the wild-type substrate.

For patients and their physicians, many aspects of the modern oncology clinical encounter remain shrouded in uncertainty. Patients seek accuracy to questions ranging from the risk of relapse after surgery with curative intent to the likelihood of responding to a prescribed chemotherapy regimen for metastatic cancer. Oncologists, unable to provide this certainty, offer an estimation of the risk or benefit derived from the analysis of large prospective clinical trials. The uncertainty arises from the inability to isolate an individual patient along the continuum of events anticipated for a group of similar patients. This disjunction between the ideal of personalized medicine and the reality of population-based practice has ramifications that extend well beyond the individual patient encounter. Consider 100 patients with stage III colon cancer. It is standard practice to offer each patient postoperative adjuvant chemotherapy.1National Institutes of HealthNIH consensus conference. Adjuvant therapy for patients with colon and rectal cancer.JAMA. 1990; 264: 1444-1450Google Scholar This recommendation is based on the observation of a 15% absolute improvement in survival demonstrated in randomized trials evaluating the addition of adjuvant therapy following surgical resection compared to surgery alone.2Moertel C.G. Fleming T.R. Macdonald J.S. Haller D.G. Laurie J.A. Tangen C.M. et al.Fluorouracil plus levamisole as effective adjuvant therapy after resection of stage III colon carcinoma A final report.Ann Intern Med. 1995; 122: 321-326Google Scholar Thus, 15 patients in this group of 100 treated patients will receive the desired benefit of treatment. The remaining 85 patients will experience a dramatically different event. For 45 of these patients, initial surgery is curative and this group is unnecessarily exposed to the morbidity and potential mortality of treatment, a decline in quality of life, and the risk of lost wages and job security. For the remaining 40 patients, an entirely different outcome is anticipated. These patients are destined to relapse with metastatic disease and the overwhelming majority will die of their cancer. For this group, adjuvant therapy is futile and novel new therapy is desperately needed. Nearly 100,000 patients will be diagnosed with early stage colon cancer in 2003. The burden to society in treating the majority of these patients as measured in the direct cost of unnecessary treatment and the indirect costs of lost productivity is enormous. The landmark report by Vogelstein3Vogelstein B. Fearon E.R. Hamilton S.R. Kem S.E. Preisinger A.C. Leppert M. et al.Genetic alterations during colorectal-tumor development.N Engl J Med. 1988; 319: 525-532Google Scholar describing the molecular events associated with the transformation of normal colon mucosa to the fully malignant phenotype was greeted with the expectation that precise answers to these troubling questions would surely follow. Unfortunately, the identification of prognostic factors (molecular or cellular features which predict for the natural history of resected colon cancer) and predictive factors (molecular or cellular features which predict for responsiveness to a prescribed chemotherapy regimen) has remained elusive. It is within this context that the report by Raffel et al4Raffel J, Bhattacharyya AK, Gallegos A, Cui H, Einspahr JG, Alberts DS. et al. Increased expression of thioredoxin-1 in human colorectal cancer is associated with decreased patient survival. J Lab Clin Med 2003;142:46-51Google Scholar should be evaluated. Thioredoxin-1 is a small redox protein. Cysteine residues at the active site cycle reversibly between oxidized and reduced forms by the action of reduced nicotinamide adenine dinucleotide phosphate–dependent flavoprotein thioredoxin reductases. A variety of activities have been attributed to thioredoxin-1, ranging from regulating the binding of redox sensitive transcription factors to deoxyribonucleic acid to the control of critical protein activity through redox-dependent binding. Laboratory studies suggest a correlation between elevated levels of thioredoxin-1 and increased tumor cell proliferation and increased cell survival through inhibition of apoptosis. Clinical studies have shown increased thioredoxin-1 expression relative to normal tissue in several human tumors. The Arizona group has previously contributed to this literature with their analysis of thioredoxin-1 levels in primary gastric cancer.5Grogan T.M. Fenoglio-Prieser C. Zeheb R. Bellamy W. Frutiger Y. Vela E. et al.Thioredoxin, a putative oncogene product, is overexpressed in gastric carcinoma and associated with increased proliferation and increased cell survival.Hum Pathol. 2000; 31: 475-481Google Scholar Raffel et al have extended their studies of thioredoxin-1 to colorectal cancer and attempt to answer three fundamental questions: (1) when in the process of malignant transformation do thioredoxin-1 levels increase; (2) is thioredoxin-1 expression a prognostic marker for survival; and (3) by inference, does thioredoxin-1 represent a target for drug discovery. Thioredoxin-1 expression was determined by immunohistochemical staining on sections cut from formalin fixed, paraffin-embedded tissues and the intensity expressed on a scale of zero (no staining) to four (very strong staining). The results are reported as a thioredoxin score, which is obtained by multiplying the intensity of staining by the fraction of cells stained. Appropriate controls and blinding were employed. To determine when levels of thioredoxin-1 increase in carcinogenesis, the investigators evaluated eight samples of normal rectal mucosa, twelve adenomatous polyps, and twelve colorectal tumors. The results suggest that elevated thioredoxin-1 expression is a late event with significantly higher levels found in colorectal tumors than in normal mucosa or polyps. The investigators used a different archival tissue set to explore the relationship of thioredoxin-1 expression to survival. A group of 37 colorectal tumors (9 stage I, 12 stage II, 8 stage III, and 8 stage IV) for which clinical annotation was available was evaluated. The investigators found no significant association between the thioredoxin-1 score and tumor location, age, sex, treatment, smoking, alcohol use, p53, or c-Erb. When adjusted for tumor stage, there was a strong inverse correlation of thioredoxin-1 score and survival (P = .012). The authors conclude that thioredoxin-1 expression is an independent marker of patient prognosis, and suggest that inhibitors of thioredoxin-1 could be useful in this group of patients.6Kirkpatrick D.L. Watson S. Kunkel M. Fletcher S. Ulhaq S. Powis G. Parallel syntheses of disulfide inhibitors of the thioredoxin redox system as potential antitumor agents.Anticancer Drug Des. 2000; 14: 421-432Google Scholar Despite numerous studies in colorectal cancer, the elucidation of precise molecular prognostic tools to guide individual treatment decisions remains incomplete. This single, retrospective study on a very small patient population is intriguing, and the conclusions drawn should be considered tentative. The hypothesis merits further evaluation in adequately powered, prospective clinical trials. If thioredoxin-1 is ultimately shown to be a prognostic factor of poor outcome for patients with colorectal cancer, and if efforts to develop an effective inhibitor are successful, this would herald the dawn of personalized medicine.

Objective: To determine the response rate, duration of response and survival with weekly gemcitabine plus docetaxel in metastatic or unresectable pancreatic cancer. Methods: Forty patients were enrolled, and 38 patients were evaluable for survival and toxicity. Thirty-seven patients were evaluable for response. Nine patients (24%) had locally advanced disease and 29 (76%) had metastatic disease at the time of enrollment. Median Eastern Cooperative Oncology Group performance status was 1. Patients received gemcitabine 750 mg/m2 i.v. and docetaxel 35 mg/m2 i.v. weekly for 3 out of 4 weeks for a maximum of 6 cycles. Results: Patients received a median of 4 cycles (range 1–6) of chemotherapy. An objective response was obtained in 10 patients (27%) with a median duration of 17 weeks. Median survival was 7 months, and 1-year survival was 19.3%. Eight patients experienced at least one form of grade 4 toxicity and 27 patients experienced at least one type of grade 3 toxicity. Conclusions: The combination of gemcitabine and docetaxel is a well-tolerated regimen with clinical efficacy. The ultimate role of this combination versus single-agent gemcitabine can only be determined by a randomized phase III trial.

(1994). Trimetrexate: A Critical Appraisal of the Phase II Clinical Trial Experience: Evidence of Drug Discovery-Clinical Development Disjunction. Cancer Investigation: Vol. 12, No. 6, pp. 657-661.

Sulofenur is a member of a new class of antineoplastic agents with a novel chemical structure and unique pharmacological and biological properties. Preclinical studies have demonstrated a wide spectrum of anti-tumor activity against murine solid tumors and human tumor xenografts. In phase I trials, only mild toxicities were observed. Twenty-six patients (pts), two of whom were inevaluable, with advanced non small cell lung cancer without prior chemotherapy were entered on this phase II trial. Pts received 800 mg/m2 sulofenur po Monday-Friday x 21 days, q 28 days. Seventeen male and 9 female pts with median performance status 1 received a median of 2 courses. Twenty pts had stage IV disease and 19 pts had adenocarcinoma, 6 squamous cell and 1 undifferentiated carcinoma. The main toxicity was grade 1 to 3 anemia in 16 (62%) pts, with hemolysis noted in 9 pts. Although methemoglobinemia was observed in 19 pts, it was severe in only 3 pts. Transient elevation of alkaline phosphatase was seen in 11 pts and one pt had a minor abnormality in glucose metabolism. Other common chemotherapy related side effects such as granulocytopenia or alopecia were not encountered with this agent. Of 24 evaluable pts, two pts had stable disease or minor response and 22 pts had progressive disease. In conclusion although sulofenur had only minor side effects, in the dosage and schedule used, it did not produce any significant response in advanced non-small cell lung cancer.

AbstractThis article presents the position‐specific introduction of substituents onto substituted phenolic rings via electrophilic destannylation of trialkylstannyl derivatives of β‐[N,N‐dialkylamino]ethoxybenzenes.

AbstractRadioiodination of p‐(trimethylstannyl)penicillin V with [125I]Na using a modification of the chloramine‐T method is simple, high yielding, and site‐specific. The structure and penicillin binding protein (PBP) affinity of p‐[125l]‐penicillin V (IPV) are similar to penicillin G and the product can be used directly without purification in the PBP assay. Because of the high degree of stability toward autoradiolysis and equivalent PBP binding affinity, IPV can be used in place of [3H]‐penicillin G or [14C]‐penicillin G for these experiments.

AbstractThe title compound (IV) is synthesized by lithiation of tamoxifen (I) with sec‐butyllithium (II) and subsequent quenching with perchloryl fluoride.

A one-step synthesis of fluorotamoxifen from tamnoxifen is described. Attempts to achieve synthesis of the title compound by fluorodestannylation or transmetallation were unsuccessful.

Radioiododestannylations was employed to prepare a series of four specifically labeled thienyl alcohols: 1-(5-iodo-2-thienyl)-cyclopentan-1-ol and -cyclohexan-1-ol; 17α-(5-iodo-2-thienyl)-17β-estradiol and -estradiol-3-O-methyl ether. The method utilized 5-(trimethylstannyl)thienyl intermediates which had been prepared in good yields from 2,5-bis(trimethylstannyl)thiophene and the appropriate cyclic ketones. The trimethylstannyl substrates reacted with no-carrier-added Na125I in the presence of 30% H2O2-acetic acid (2:1) at pH 4.5 at ambient temperature for 5–15 min to give, after HPLC separation, the desired 5-[125I]iodothien-2-yl products in greater than 90% isolated yields. Although tissue distribution studies in rats were uneventful, the methodology employed to give the labeled products possesses distinct advantages compared to alternative methods for preparing radioiodinated aryl moieties.

Monotransmetallation of 2,5-bis(trimethylstannyl)thiophene followed by the addition of estrone 3-methyl ether and iodine yields 3-methoxy-17α,-(5-iodothien-2-yl)estra-1,3,5(10)trien-17β-ol.

Abstract5‐Trimethylstannyl‐furanä‐lithium (I) addiert an Cycloalkanone (II) zu den Alkoholen (III), deren Trimethylstannyl‐ Gruppierung mit lod unter Bildung von (IV) ausgetauscht wird.

17α-E-Iodovinylestradiol and its iodine-125-labeled analog were prepared by halodestannylation. The synthesis of the unlabeled compound was achieved from estrone in two steps with an overall yield of 30%. The tributylstannylvinylestradiol intermediate reacted with sodium [125I]iodide (specific activity = 2200 Ci/mmol) in the presence of hydrogen peroxide and acetic acid to give the 17α-E-[125I]iodovinylestradiol in 40–60% yield after isolation by reversed phase column chromatography. The radiochemical purity was greater than 98% and no other u.v. active components could be detected by HPLC. The ease of preparation and isolation of this radioligand suggests that radiohalodestannylation may be the method of choice for this and structurally similar compounds.

Abstract Procedures for the synthesis of chloro- and iodo-methyltributyltin and tributylstannylmethyl methanesulfonate from tributyltin hydride are described.

Abstract The synthesis of the 2,5-bis(trimethylstannyl) derivatives of thiophene and furan is reported. Conditions for monotransmetalation and electrophilic destannylation are described.