Novel acid labile COL1 trityl-linked difluoronucleoside immunoconjugates: synthesis, characterization, and biological activity.

LY207702 (1) is a difluorinated purine nucleoside that exhibits impressive antitumor activity in preclinical models. This agent, however, also possesses cardiotoxicity which limits the potential clinical utility of this novel drug candidate. We therefore developed linker chemistry whereby regioselective N6-tritylation of LY207702 (1) allowed this drug to be coupled to epsilon-lysine amino groups of mAb's reactive with human tumor-associated antigens. The resulting immunoconjugates 3 possessed conjugation ratios ranging from 5 to 7 mol of LY207702/mol of mAb, minimal aggregate content (5-10%), and good immunoreactivity. The electronic nature of substituents on the aromatic rings of the trityl group dictated the degree of acid lability of the trityl linker. Increased electronic stabilization of the transient trityl carbocation led to increase in the release rate of free drug, i.e., m-DMT 10a = p-DMT 10b > p-MMT 10d > p-T 10f. Consequently, the more acid labile DMT conjugates 3a and 3b proved to be the most potent cytotoxic agents, and the most stable p-T conjugate 3f exhibited the least antitumor activity when evaluated in vitro and in vivo. p-MeT-linked conjugate 3e, the most stable construct that retained excellent in vivo antitumor activity, was selected for more extensive evaluation. No detectable free drug or metabolite was observed in mouse plasma at a single intravenous dose of p-MeT conjugate 3e, which was consistent with its predicted stability under physiological conditions. This construct did, however, exhibit significant antigen-mediated antitumor activity in vivo. No cardiotoxicity was detected in mice dosed with conjugate 3e (6 mg/kg free drug content per day for 21 days) equivalent to approximately 8 times the total dose required for complete regression of well-established (approximately 1 g) HC1 human colon tumor xenografts in nude mice. Cardiotoxicity was induced in 20% of free drug 1 treated group at the equivalent dose. Cardiomyopathy was, however, observed when the dose of conjugate 3e was increased to 8 mg/kg per day for 21 days. These data suggest that antitumor activity of LY207702 (1) was maintained and its cardiotoxic potential reduced when this agent was administered to human tumor xenograft bearing nude mice as COL1-N6-p-MeT-207702 conjugate 3e.

In vivo expression of P-glycoprotein in a human colon carcinoma xenograft is modulated by therapy with free and monoclonal antibody-conjugated vinca alkaloids.

Well established UCLA-P3 human lung tumor xenografts were significantly regressed by treatment with a monoclonal antibody-vinca immunoconjugate whereas no regressions were observed for the LS174T and SW948 human colon carcinoma xenografts by this therapy. Antibody and complementary DNA probes utilized for detection of the MDR1 gene product and mRNA levels, respectively, revealed that prior to drug treatment the lung tumor had virtually no detectable P-glycoprotein while both colon carcinomas displayed low and heterogeneous expression of this resistance-related protein. It was subsequently determined, however, that the low level of P-glyocoprotein expression observed for one of the colon tumors could be rapidly modulated following therapy with free or MoAb-conjugated vinca. These data indicated that elevated P-glycoprotein levels resulting from drug therapy may play a role in the lack of regression of the human colon xenografts. Most significantly, our results also indicated that the time interval between drug treatment and tissue sampling may be a critical factor to be considered in studies which attempt to correlate P-glycoprotein expression with chemotherapy.

Test-retest reliability of the Profile of Mood States using visually impaired athletes.

The test-retest reliabilities of the Profile of Mood States when items were read aloud on consecutive days to 15 nationally ranked visually impaired athletes ranged from .78 to .95, so the scale can be used with visually impaired athletes who cannot complete the profile in the traditional written manner.

Repeated suppression of lymphocyte blastogenesis following vaccinations of CPV-immune dogs with modified-live CPV vaccines.

A commercially available modified-live canine parvovirus (CPV) vaccine was evaluated for its immunosuppressive properties in eight random-bred dogs, all with circulatory antibody to CPV. Three of the eight dogs exhibited a significant decrease in lymphocyte blastogenesis after vaccine administration. In these dogs, this decrease in blastogenesis was of short duration and was consistently observed after repeated administrations of the vaccine. Neither gastroenteritis, fever nor leukopenia, signs indicative of virulent canine parvovirus infection, were detected in these animals. In addition, lymphocytes from these dogs lacked Ia antigen expression. This study demonstrated that the immunomodulating effects of ML-CPV is not observed in all animals yet is consistent in affected individuals.

Influence of coactors on performance of visually impaired runners.

The purpose of this exploratory study was to determine the influence of coactors on the running performance of 13 visually impaired individuals. There was no significant difference for visually impaired sprint runners running alone and with a coactor. The "mere presence" of a coactor was not enough for social facilitation to occur when visual evaluation was not present.

Feline leukemia vaccine: efficacy, contents and probable mechanism.

An effective subunit vaccine against feline leukemia virus infection and related diseases has been developed. The source of the vaccine immunogen is feline retrovirus persistently infected cells that continuously synthesize and shed virus polypeptides. Western blot analysis identifies FeLV-gp70, p27, p15, p12, and p10 in the subunit vaccine preparation. Cats immunized with the vaccine developed antibodies to a 70,000 MW protein of the vaccine that seems to be distinct from, but related to the FeLV-gp70 polypeptide.

Use of the State-Trait Anxiety Inventory for visually impaired athletes.

This report detailed the reliability of the State-Trait Anxiety Inventory when the test statements were presented verbally and in the traditional manner to undergraduates, 19 men and 17 women, who were physical education majors. In the standardized manner subjects read the statements silently to themselves; in the other administration statements were read aloud. The inventory then was administered twice verbally to 15 elite visually impaired women athletes. Both the state and trait subscales of this inventory are reliable if presented across or within modalities. The inventory, when presented verbally, might be appropriately used by visually impaired athletes in psychological preparation prior to competition.