Can butyrate prevent colon cancer? The AusFAP study: A randomised, crossover clinical trial.

Increased colonic butyrate from microbial fermentation of fibre may protect from colorectal cancer (CRC). Dietary butyrylated high amylose maize starch (HAMSB) delivers butyrate to the large bowel. The objective of this clinical trial (AusFAP) is to evaluate potential chemoprotective effects of HAMSB on polyposis in individuals with a genetic form of colon cancer, Familial Adenomatous Polyposis (FAP).

Enabling Nurse-Patient Communication With a Mobile App: Controlled Pretest-Posttest Study With Nurses and Non-English-Speaking Patients.

Background: There is growing concern regarding the implications of miscommunication in health care settings, the results of which can have serious detrimental impacts on patient safety and health outcomes. Effective communication between nurses and patients is integral in the delivery of timely, competent, and safe care. In a hospital environment where care is delivered 24 hours a day, interpreters are not always available.

Developing Digital Facilitation of Assessments in the Absence of an Interpreter: Participatory Design and Feasibility Evaluation With Allied Health Groups.

Background: To ensure appropriate and timely care, interpreters are often required to aid communication between clinicians and patients from non-English speaking backgrounds. In a hospital environment, where care is delivered 24 hours a day, interpreters are not always available. Subsequently, culturally and linguistically diverse (CALD) patients are sometimes unable to access timely assessment because of clinicians' inability to communicate directly with them.

CALD Assist-Nursing: Improving communication in the absence of interpreters.

Aims And Objectives: To develop a communication app to support nursing staff during the provision of standard care of patients from non-English-speaking backgrounds (NESBs), when an interpreter is not available. This paper reports on the user needs analysis phase that informed the development, content and functionality of the app.

Background: In 2014 we developed CALD Assist, a communication app to support patient interactions with allied health clinicians when interpreters are not present.

Designing Technology for Assessments of CALD Patients.

Interpreters are required to aid communication between clinicians and culturally and linguistically diverse (CALD) patients to ensure appropriate and timely care. Demand for interpreting services however, often exceeds supply. A mobile app to translate clinical assessment questions in 10 common languages using pictorial, written and voice-over prompts to assist patient assessments when interpreters are unavailable has been developed.

Genomic imbalances associated with acquired resistance to platinum analogues.

During the past several years, a panel of human tumor cell lines (predominantly ovarian) with acquired resistance to cisplatin, the orally bioavailable analogue JM216, and the structurally hindered analogue AMD473, has been established and characterized for underlying mechanisms of resistance. We have examined these resistant cell lines for gains and losses of DNA associated with the acquisition of resistance using the molecular cytogenetic technique of comparative genomic hybridization. Our comparison of three analogues has shown the most frequently observed changes to include amplification of 4q (5/7) and 6q (5/7), followed by amplification of 5q (3/7).

Phase I and pharmacokinetic study of an oral platinum complex given daily for 5 days in patients with cancer.

Purpose: We aimed to determine the maximum-tolerated dose (MTD) clinical toxicities, pharmacokinetics, and pharmacodynamics of oral JM216 given once daily for 5 days to cancer patients.

Patients And Methods: Patients who fulfilled standard phase I trial criteria were enrolled. Oral JM216 was given at doses based on patient body-surface area, on an empty stomach, once daily for 5 consecutive days, as 10-, 50-, and 200-mg hard gelatin capsules and with oral antiemetics.

The cytotoxic action of four ammine/amine platinum(IV) dicarboxylates: a flow cytometric study.

We have used flow cytometry to study the mechanism of cytotoxic action of a series of ammine/amine Pt(IV) dicarboxylates [ammine diacetatodichloro(cyclohexylamine) platinum(IV), JM216; ammine dibutyratodichloro(cyclohexylamine)platinum(IV), JM221; ammine diacetatodichloro(propylamine)platinum(IV), JM223; ammine dibenzoatodichloro(propylamine)platinum(IV), JM244]. JM216 has been shown to have clinical potential and has recently entered phase II trials. All the compounds caused a slowdown in S-phase transit followed by a block in G2.

Phase I trial of ZD1694, a new folate-based thymidylate synthase inhibitor, in patients with solid tumors.

Purpose: To perform a phase I clinical and pharmacologic study of ZD1694 (Tomudex, Alderley Park, United Kingdom), a new folate-based thymidylate synthase (TS) inhibitor, in patients with advanced malignancy.

Patients And Methods: From February 1991 to January 1993, 61 patients with a range of solid tumor received 161 courses of ZD1694 given as a single 15-minute intravenous infusion every 3 weeks, at escalating doses from 0.1 to 3.

Tomudex (ZD1694): from concept to care, a programme in rational drug discovery.

Folate-based anticancer drugs with specificity for thymidylate synthase (TS) have come of age. Ideas nurtured in the early 1970s led to the first-generation of antifolates with TS and dihydrofolate reductase (DHFR) inhibitory activities. Compounds with increased selectivity for TS followed with the highly specific inhibitor, CB3717 being synthesised in 1979 at the Institute of Cancer Research (ICR).

Preclinical pharmacology and antitumour activity of the novel sequence-selective DNA minor-groove cross-linking agent DSB-120.

We examined the in vitro cytotoxicity, antitumour activity and preclinical pharmacokinetics of the novel sequence-selective, bifunctional alkylating agent DSB-120, a synthetic pyrrolo[1,4][2,1-c]benzodiazepine dimer. DSB-120 was shown to be a potent cytotoxic agent in vitro against a panel of human colon carcinomas [50% growth-inhibitory concentration (IC50) 42 +/- 7.9 nM, mean +/- SE, n = 7] and two rodent tumours (L1210 and ADJ/PC6).

Biotransformation of the platinum drug JM216 following oral administration to cancer patients.

This study evaluates the metabolic profile of JM216 [bis(acetato)ammine-dichloro(cyclohexylamine) platinum(IV)], the first orally administrable platinum complex, in plasma ultrafiltrates of 12 patients (n = 2-4 time points per patient) following different doses of drug (120, 200, 340, 420, 560 mg/m2). The biotransformation profile was evaluated by high-performance liquid chromatography (HPLC) followed by atomic absorption spectrophotometry (AA). The AA profiles were compared with those previously identified by HPLC on line with mass spectrometry (HPLC-MS) in plasma incubated with JM216.

Novel trans platinum complexes: comparative in vitro and in vivo activity against platinum-sensitive and resistant murine tumours.

Two pairs of cis/trans platinum complexes, JM118 (cis-ammine(cyclohexylamine) dichloro platinum(II)) and its trans counterpart, JM334 and JM149 (cis-ammine(cyclohexylamine) dichloro-dihydroxo platinum(IV)) and its trans counterpart JM335 have been evaluated (both in vitro and in vivo) against two murine tumour models of historical importance in the discovery of novel platinum drugs; the ADJ/PC6 plasmacytoma and the L1210 leukaemia and sublines selected for resistance to platinum drugs. In vitro, results showed that the trans complexes induced comparable growth inhibitory properties to those observed for cisplatin and their respective cis isomers. Moreover, retention of activity was observed in a series of 5 acquired platinum drug (cisplatin, carboplatin, iproplatin, tetraplatin and JM149)-resistant L1210 sublines whereas at least partial cross-resistance was observed to the cis isomer JM149 in the acquired carboplatin and iproplatin-resistant lines (in addition to being 11-fold resistant in the line selected for resistance to JM149 itself).

cis-Diamminedichloroplatinum(II)-induced cell death through apoptosis in sensitive and resistant human ovarian carcinoma cell lines.

We have studied the effects of the chemotherapeutic drug cis-diamminedichloroplatinum(II) (cis-platin) on three human ovarian carcinoma cell lines - one sensitive to the drug (CH1), one with acquired resistance (CH1cisR) and one with intrinsic resistance (SKOV-3). Previous work has shown that the 50% inhibitory concentrations (IC50 values) after a 2-h exposure to the drug are: CH1, 2.5 microM; CH1cisR, 7.

Determination of metabolites of a novel platinum anticancer drug JM216 in human plasma ultrafiltrates.

The present study describes the application of on-line liquid chromatography-electrospray ionisation in conjunction with a high resolution magnetic sector mass spectrometer to identify metabolites of a platinum(IV) anticancer drug JM216 [bis(acetato)amminedichloro(cyclohexylamine)platinum(IV)] in human plasma. Four metabolites were identified following incubation of JM216 in human plasma: JM118 [amminedichlorocyclohexylamineplatinum(II)], a platinum(II) complex; JM383 [bis(acetato)amminedihydroxo(cyclohexylamine)platinum(IV)]; JM518 [bis(acetato)amminechloro(cyclohexylamine)hydroxoplatinum (IV)] and its isomer JM559. The platinum complexes mass spectra were dominated by the natriated [M + Na]+ ion.

Metabolic studies of an orally active platinum anticancer drug by liquid chromatography-electrospray ionization mass spectrometry.

Bis(acetato)amminedichloro(cyclohexylamine) platinum(IV) (JM216) is a new orally administered platinum complex with antitumor properties, and is currently undergoing phase II clinical trials. When JM216 was incubated with human plasma ultrafiltrate, 93% of the platinum species were protein-bound and 7% were unbound. The unbound platinum complexes in the ultrafiltrates of human plasma were analysed using a liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS) method.

Initiatives with platinum- and quinazoline-based antitumor molecules--Fourteenth Bruce F. Cain Memorial Award Lecture.

Carboplatin is a better-tolerated alternative to cisplatin. JM216, the first p.o.

ZD1694 (Tomudex): a new thymidylate synthase inhibitor with activity in colorectal cancer.

ZD1694 (Tomudex) is a new antifolate which is a specific inhibitor of thymidylate synthase (TS). Evidence suggests that ZD1694 has a spectrum of activity that only partially overlaps with 5-fluorouracil (modulated with leucovorin) against colon tumours in vitro. Potent cytotoxic activity is dependent upon active uptake into cells via the reduced folate/methotrexate cell membrane carrier (RFC) and subsequent metabolism to polyglutamated forms (tri, tetra and pentaglutamates).

2'-Deoxycytidine kinase deficiency is a major determinant of 2-chloro-2'-deoxyadenosine resistance in lymphoid cell lines.

2-Chloro-2'-deoxyadenosine, (CldAdo) resistance was developed in the W1L2 human B lymphoblastoid (resistance factor, 160) and L1210 murine leukemia (resistance factor, 605) cell lines by continuous exposure to CldAdo. Cross-resistance studies showed that while the variant lines generally retained sensitivities to 9-beta-D-arabinofuranosyladenine (in the presence of 2'-deoxycoformycin), hydroxyurea, and Adriamycin, both were highly cross-resistant to 1-beta-D-arabinofuranosylcytosine (ara-C), 2', 2'-difluorodeoxycytidine, and 9-beta-D-arabinofuranosyl-2-fluoroadenine. Measurement of both phosphorylating and degrading enzyme activities demonstrated that initial phosphorylation of CldAdo and 2'-deoxycytidine were severely impaired in cell extracts from the resistant lines, whereas adenosine kinase activity remained unaffected and there was no apparent increase in cytoplasmic deoxynucleotidase activity using dCMP as substrate.

A novel trans-platinum coordination complex possessing in vitro and in vivo antitumor activity.

As part of a drug discovery program to discover more effective platinum-based anticancer drugs, a series of platinum complexes of trans coordination geometry centered on trans-ammine(cyclohexylaminedichlorodihydroxo)platinum(IV) (JM335) has been evaluated in vitro against a panel of cisplatin-sensitive and cisplatin-resistant human tumor cell lines (predominantly ovarian). In vitro, against 5 human ovarian carcinoma cell lines, JM335 was comparably cytotoxic to cisplatin itself and over 50-fold more potent than transplatin (mean 50% inhibitory concentrations: JM335, 3.1 microM; cisplatin, 4.

Circumvention of acquired tetraplatin resistance in a human ovarian carcinoma cell line by a novel trans platinum complex, JM335 [trans ammine (cyclohexylamine) dichloro dihydroxo platinum (IV)].

Acquired resistance to tetraplatin [d,1-trans-1,2-diaminocy-clohexane tetrachloroplatinum (IV)] has been generated in vitro in the human ovarian carcinoma cell line PXN94; the derived line, PXN94tetR, was 24-fold resistant to tetraplatin. Intracellular tetraplatin accumulation was reduced in PXN94tetR compared with PXN94 by an average of 1.3-fold across the concentration range 1-100 microM (2 hr exposure).

Evaluation of novel ammine/amine platinum (IV) dicarboxylates in L1210 murine leukaemia cells sensitive and resistant to cisplatin, tetraplatin or carboplatin.

Seventeen alkylamine ammine dicarboxylatodichloroplatinum(IV) complexes of general structure c,t,c-[PtCl2(OCOR1)2NH3(RNH2)], where R = aliphatic or alicyclic and R1 = aliphatic or aromatic, have been evaluated against L1210 cell lines with acquired resistance to cisplatin (10-fold), tetraplatin (34-fold) or carboplatin (14-fold) using an in vitro growth-delay assay. All of these compounds overcame cisplatin, tetraplatin and carboplatin resistance. Potency increased as the number of carbon atoms in the axial aliphatic ligands (R1) increased, for example comparing JM216 (R = cyclohexyl, R1 = CH3, IC50 = 1.

Schedule dependency of orally administered bis-acetato-ammine-dichloro-cyclohexylamine-platinum(IV) (JM216) in vivo.

JM216 is a novel antitumor platinum(IV) complex displaying oral activity, dose-limiting myelosuppression, and a lack of nephro- and neurotoxicity in rodents. It has been selected for clinical evaluation. The schedule dependency of its antitumor action against a murine (ADJ/PC6 plasmacytoma) and a human tumor model (PXN109T/C ovarian carcinoma xenograft) was studied in vivo.

Cisplatin induces apoptosis in a human ovarian carcinoma cell line without concomitant internucleosomal degradation of DNA.

After treatment of the human ovarian carcinoma cell line, CH1, with cisplatin, cells detached from the culture dish in a time- and dose-dependent fashion. These cells showed morphological changes indicative of apoptosis. Their DNA had not been degraded into oligonucleosomal fragments, but the DNA had been cut into larger fragments (30 kbp) of a size associated with chromatin loops.