Biomedical subjects
Publications and source records attributed to G Y Locker.
Since patients exhibit both acute and chronic cardiac toxic effects from Adriamycin, the salient characteristics of the reported animal models for both acute and chronic cardiotoxicity are reviewed. This review reveals that while the pathology of these models is often well-characterized, the physiologic, biochemical, and nutritional variables are, in general, poorly defined.
The metastatic spread of a trnasplantable murine ovarian cancer is similar to the spread of ovarian cancer in patients with advanced disease, making it a useful model to investigate novel experimental therapies. The ip inoculation of 10(6) tumor cells into C3HeB/FeJ mice leads to the formation of ascites, sub-diaphragmatic tumor deposits, intra-abdominal tumors, and death within 25 days. Adriamycin (ADR) was found to be an active agent against this murine ovarian cancer. The effects of ADR were dependent upon the route of administration. A single ip LD10 dose of ADR (5 mg/kg) administered 2 days after inoculation with 10(6) tumor cells produced long-term survival (greater than 60 days) in 70% of the mice. An iv LD10 dose had no effect on survival. The survival advantage of ip ADR (compared to the iv route) was found to be related to: (a) a greater suppression of DNA synthesis in the tumor; (b) a rapid penetration of ADR into the nuclei of ascites tumor cells and into sub-diaphragmatic tumor deposits; and (c) significantly higher levels of ADR in tumor cells following ip administration. The ip route may also be less cardiotoxic since the peak levels after an iv dose were three times greater than after an equal ip dose. If local toxicity does not prove to be a major problem, then ip ADR may be a useful mode of therapy in patients with intra-abdominal tumors.
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The effect of the antitumor antibiotic doxorubicin on glutathione and glutathione disulfide levels in mouse heart and liver has been evaluated. The glutathione content of hepatic and cardiac tissue from saline-treated controls exhibited a statistically significant diurnal variation. Doxorubicin administration produced a dose-related decrease in hepatic glutathione which was not blocked by pretreatment with the free radical scavenger alpha-tocopherol; a lesser drop in cardiac glutathione was also documented. These changes may play an important role in the metabolism and toxicity of doxorubicin.
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The standard adjuvant endocrine treatment for postmenopausal women with hormone-receptor-positive localised breast cancer is 5 years of tamoxifen, but recurrences and side-effects restrict its usefulness. The aromatase inhibitor anastrozole was compared with tamoxifen for 5 years in 9366 postmenopausal women with localised breast cancer. After a median follow-up of 68 months, anastrozole significantly prolonged disease-free survival (575 events with anastrozole vs 651 with tamoxifen, hazard ratio 0.87, 95% CI 0.78-0.97, p=0.01) and time-to-recurrence (402 vs 498, 0.79, 0.70-0.90, p=0.0005), and significantly reduced distant metastases (324 vs 375, 0.86, 0.74-0.99, p=0.04) and contralateral breast cancers (35 vs 59, 42% reduction, 12-62, p=0.01). Almost all patients have completed their scheduled treatment, and fewer withdrawals occurred with anastrozole than with tamoxifen. Anastrozole was also associated with fewer side-effects than tamoxifen, especially gynaecological problems and vascular events, but arthralgia and fractures were increased. Anastrozole should be the preferred initial treatment for postmenopausal women with localised hormone-receptor-positive breast cancer.
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