New Marine Derived Anticancer Therapeutics ─ A Journey from the Sea to Clinical Trials

Nature has been instrumental as a source for therapeutics. Despite the fact that we live in an oceanic planet, a number of technical factors have historically hampered the evolution of a marine-based chamanic medicine. With the implementation of scuba diving tools and the development of sophisticated instruments for the isolation and elucidation of structures of natural products from marine organisms, major advances have been made in the discovery of marine derived therapeutics. The availability of ARA-C, a nucleoside analog that is a basic component in the treatment of acute myeloid leukemia, and its fluorinated analog Gemcitabine, an important therapeutic tool in the treatment of pancreatic cancer and in non small cell lung cancer, is a solid proof and validation of the potential of this approach. As a result of our discovery and developmental program, three innovative compounds with novel mechanisms of action: ET-743, Aplidin^R and Kahalalide F, have been shown to display a positive therapeutic index and activity in resistant solid tumors that supports the ongoing clinical phase III/II trials. ET-743 represents the first active agent against sarcomas developed in the past 25 years and has demonstrated a therapeutic potential in pretreated ovarian cancer. Several chemical entities are under advanced preclinical testing and additional candidates for clinical development are emerging, including compounds hitting a specific target. Moreover, the development of a given marine candidate implies the collaboration of an interdisciplinary team special focused on supply, formulation, pharmacogenetics and preclinical toxicology.     

Validation of actigraphy to assess circadian organization and sleep quality in patients with advanced lung cancer

Background

Many previous studies have documented seasonal variation in suicides globally. We re-assessed the seasonal variation of suicides in Finland and tried to relate it to the seasonal variation in daylength and ambient temperature and in the discrepancy between local time and solar time.

Methods

The daily data of all suicides from 1969 to 2003 in Finland (N = 43,393) were available. The calendar year was divided into twelve periods according to the length of daylight and the routinely changing time difference between sun time and official time. The daily mean of suicide mortality was calculated for each of these periods and the 95% confidence intervals of the daily means were used to evaluate the statistical significance of the means. In addition, daily changes in sunshine hours and mean temperature were compared to the daily means of suicide mortality in two locations during these afore mentioned periods.

Results

A significant peak of the daily mean value of suicide mortality occurred in Finland between May 15th and July 25th, a period that lies symmetrically around the solstice. Concerning the suicide mortality among men in the northern location (Oulu), the peak was postponed as compared with the southern location (Helsinki). The daily variation in temperature or in sunshine did not have significant association with suicide mortality in these two locations.

Conclusions

The period with the longest length of the day associated with the increased suicide mortality. Furthermore, since the peak of suicide mortality seems to manifest later during the year in the north, some other physical or biological signals, besides the variation in daylight, may be involved. In order to have novel means for suicide prevention, the assessment of susceptibility to the circadian misalignment might help.     

Vetch toxicosis in cattle grazing Vicia villosa ssp dasycarpa and V benghalensis

SUMMARY The epidemiological, clinical and pathological features of a disease syndrome in adult cattle grazing woolly-pod vetch (Vicia villosa ssp dasycarpa) or popany vetch (V benghalensis) are reported. Outbreaks of toxlcosis occurred between midwinter and midsummer in 3 dairy and 6 beef herds on the north coast of New South Wales, between 1982 and 1992. Friesian, Angus, Murray Grey, Guernsey and Hereford breeds were affected. Mean morbidity and case fatality rates in affected herds were 7% (65 of 889) and 69%, respectively. Signs of pruritic dermatitis, illthrift and death were associated with an eosinophilic granulomatous inflammation of many organs, particularly involving the renal cortex, dermis, myocardium, adrenal glands, lymph nodes and hepatic portal triads.     

Seroprevalence of equine herpesvirus 1 in Thoroughbred foals before and after weaning

Objective To investigate the seroprevalence of equine herpesvirus 1 in foals around weaning and after weaning on two large Thoroughbred farms using a type-specific enzyme-linked immunosorbent assay to determine exposure to infection.
Design A longitudinal population study in groups of Thoroughbred weanling foals.
Study population Two hundred weanling Thoroughbred foals from a population of about 380 foals were enrolled on two adjacent stud farms in the Hunter Valley of New South Wales. Foals on both farms were weaned from February to May 1995 into randomly selected groups of 10 to 15 foals. Farms were selected because of their willingness to cooperate in the survey and because their detailed records of foals and their movements. They were representative of well-managed large Thoroughbred stud farms in New South Wales. Both studs had upper respiratory tract disease among weanling foals around weaning each year although the sero-prevalence of viral respiratory disease on either farm was not known before the study.
Procedure Serum was collected from foals within each group at fortnightly intervals from 9th February until 1st June 1995, and at a single follow-up period in August 1995. Each sample was tested in triplicate using an antibody-detection ELISA which is type-specific for EHV-1 and EHV-4 antibodies.
Results and conclusions There was serological evidence of EHV-1 infection both before and after weaning. The prevalence of EHV-1 antibody in the sample population increased during the study and individual cases of EHV-1 infection were identified. The increase was caused both by the seroconversion of foals within the groups and by the recruitment into the study of foals with pre-existing EHV-1 antibody. Evidence of EHV-1 infection in Thoroughbred foals after weaning has not been reported previously in Australia and this has implications for vaccination regimens.     

Mercury contamination of the harbour porpoise Phocoena phocoena and other cetaceans from the North Sea and the kattegat

Total Hg levels were determined in 17 harbour porpoises Phocoena phocoena collected in the North Sea and the Kattegat (muscle, liver and kidney), as well as in a sperm whale Physeter macrocephalus, a common dolphin Delphinus delphis and two bottle-nose dolphins Tursiops truncatus collected in Belgium. Juvenile porpoises (total body length less than 140 cm) were characterized by total Hg concentrations increasing with length (t.i. with age) with median values of 3.1 μg g^?1 dw in muscle, 6.2 in liver and 5.7 in kidney, and liver to muscle resp. liver to kidney ratios varying between 1 and 2. In adults, liver concentrations were higher (up to 500 μg g^?1 dw) with liver to muscle and to kidney ratios up to 20. Median McHg concentrations in 5 of the porpoises were 4.0 μg g^?1 dw in muscle and 6.9 in liver. These values did not increase as strongly with length (t.i. with age, at least for juveniles) as total Hg did; as a consequence, the relative McHg levels decreased from 100% in juveniles to 2 or 3 % in the liver of adults. Such results seem to reflect the existence of a slow mineralization phenomenon and storage of inorganic Hg, mainly in the liver.     

Redox cycling induces spermptosis and necrosis in stallion spermatozoa while the hydroxyl radical (OH•) only induces spermptosis

Oxidative stress is a major factor explaining sperm dysfunction of spermatozoa surviving freezing and thawing and is also considered a major inducer of a special form of apoptosis, visible after thawing, in cryopreserved spermatozoa. To obtain further insights into the link between oxidative stress and the induction of apoptotic changes, stallion spermatozoa were induced to oxidative stress through redox cycling after exposure to 2‐methyl‐1,4‐naphthoquinone (menadione), or hydroxyl radical formation after FeSO₄ exposure. Either exposure induced significant increases (p < 0.05) in two markers of lipid peroxidation: 8‐iso‐PGF_2α and 4‐hydroxynonenal (4‐HNE). While both treatments induced changes indicative of spermptosis (caspase‐3 activation and decreased mitochondrial membrane potential) (p < 0.01), menadione induced sperm necrosis and a dramatic reduction in motility and thiol content in stallion spermatozoa. Thus, we provided evidence that oxidative stress underlies spermptosis, and thiol content is a key factor for stallion sperm function.     

Dose–Response Studies for Pituitary and Testicular Function in Male Dogs Treated with the GnRH Superagonist, Deslorelin

We tested the effect of dose of GnRH superagonist on pituitary and testicular function in a study with four groups of four male dogs. The Controls received blank implants and the other three groups received implants containing 3, 6 or 12 mg deslorelin (d ‐Trp⁶‐Pro⁹‐des‐Gly¹⁰‐GnRH ethylamide). In all deslorelin‐treated groups, there was initially an acute increase in plasma concentrations of LH and testosterone, followed by declines such that both hormones became undetectable after approximately 12 days. There was a dose–response in some of these early aspects of the hormone profiles. With respect to long‐term effects of treatment, the 12‐mg dose had significantly greater effects than the smaller doses for the duration of minimum testicular volume [366 ± 77, mean ± SEM (3 mg), 472 ± 74 (6 mg), and 634 ± 59 (12 mg) days], absence of ejaculate [416 ± 88 (3 mg), 476 ± 83 (6 mg), and 644 ± 67 (12 mg) days], undetectable plasma concentrations of LH and testosterone [367 ± 64 (3 mg), 419 ± 72 (6 mg), and 607 ± 69 (12 mg) days], the delay until complete recovery of LH and testosterone secretion [394 ± 65 (3 mg), 484 ± 72 (6 mg) and 668 ± 47 (12 mg) days], and the delay until testes had regrown to normal volume [408 ± 77 (3 mg), 514 ± 74 (6 mg), 676 ± 59 (12 mg) days]. The time taken to restore full ejaculates was also longest for the 12‐mg dose: 716 ± 67 (12 mg) days vs 440 ± 66 (3 mg) and 538 ± 83 (6 mg) days after implantation. There was no correlation between delay to recovery of normal ejaculate quality and body mass. We conclude that the dose–response relationship with deslorelin implants is not expressed with respect to the degree of suppression of reproduction, but on the maximum duration of suppression and thus to delay until recovery.