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S D Harrison

Publications and source records attributed to S D Harrison.

80 records · Page 5Linked to original sources
PubMedDate not supplied

Binding of the epoxide cryptophycin analog, LY355703 to albumin and its effect on in vitro antiproliferative activity.

Cryptophycin, isolated from the cyanobacterium Nostoc, is a cytotoxic dioxadiazacyclohexadecenetetrone which causes rapid depletion of microtubules in intact cells. In the present report, the effect of protein binding of a new synthetic cryptophycin analog, LY355703 (cryptophycin 52), is discussed. In handling the compound, it was found to bind extensively to surfaces, and a high degree of plasma protein binding was also observed (about 99% in human plasma). Similarly, while LY355703 displays potent antiproliferative activity against several human tumor cell lines in vitro (IC50s ranging from 12 to 40 pM), the addition of human or bovine serum albumin (BSA) to CCRF-CEM cells adapted to serum-free (UltraCHO) medium markedly reduced its anti-proliferative activity. For example, the IC50s for LY355703 in BSA at 0, 4 and 40 mg/ml were 2, 19 and 34 pM, respectively. In comparison, the IC50 only increased 2-fold (4210-8530 pM) for taxol over the same BSA concentration range. When log phase CCRF-CEM cells were exposed to 1 microM [3H]LY355703, there was a rapid accumulation of drug, so that LY355703 reached steady state within 10 min. The rate of LY355703 uptake in log-phase CCRF-CEM human leukemia cells was a linear function of concentration over a wide range (0.25-50 microM), although the cytotoxicity IC50 was 19 pM. Drug accumulation was not inhibited by sodium azide. Although cryptophycin was observed to bind extensively to albumin, binding did not markedly modulate cryptophycin uptake by CCRF-CEM cells. Overall, these results demonstrate that attention must be given to the binding properties of LY355703 and similar cryptophycins while handling these compounds, and that binding to albumin (and probably other cellular components as well) is a significant factor for interpretation of results both in vitro and in vivo.

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PubMedDate not supplied

Toxicologic evaluation of cis-diamminedichloroplatinum II in B6D2F1 mice.

The purpose of this study was to evaluate the toxicologic responses of mice to cis-diammine-dichloroplatinum II (cis-DDP), an established antitumor drug, and compare them to those reported in rats, dogs, and monkeys. This comparison would facilitate the continuing appraisal of the usefulness and reliability of the mouse to predict the toxicologic response to antitumor drugs in human patients. In duplicate experiments, B6D2F1 mice were treated with 8, 10, 12, and 14 mg/kg of cis-DDP in single, intraperitoneal doses. These sublethal doses corresponded to 0.4, 0.5, 0.7, and 0.8 LD50. On posttreatment days 1, 3, 6, 10, 14 or 15, and 21 or 22, groups of mice were killed and blood and other tissues were collected for hematologic (8 tests), clinical chemical (11 tests), and histopathologic (11 tissues) evaluations. Cis-DDP induced reticulocytopenia, azotemia, renal tubular necrosis and damage to the gastrointestinal epithelium with the severity being dose dependent. Hematopoietic and gastrointestinal alterations were reversible. Renal lesions were still apparent 21 days posttreatment. Although the cis-DDP doses used in this study were lower than doses used in studies with other species, the organ lesions in mice were similar to those observed in rats, dogs, or monkeys. The use of the mouse offers a number of advantages for pharmaceutical and chemical development programs, but additional data will be required to assess the overall reliability of the mouse for predicting target organs of antitumor drugs and other xenobiotics in man.

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