Biomedical subjects
Publications and source records attributed to K Hellmann.
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Dexrazoxane combined with doxorubicin (+ 5-fluorouracil + cyclophosphamide - the FAC regime) leads to a significant decrease in doxorubicin cardiotoxicity and a significant increase in median survival time for patients with advanced breast cancer responsive to FAC. The reason for this increase in survival may be due to interference with the mechanism involved in the emergence of multidrug resistance (MDR). In order to test this hypothesis, we induced resistance to doxorubicin in the K562 cell line by growing cells in increasing concentrations of doxorubicin (10-30 nM) in the presence and absence of dexrazoxane (20 nM). The doxorubicin sensitivity of all resultant sublines was measured using the MTT assay. Flow cytometry was used to assess the MDR1 phenotype, measuring P-glycoprotein expression with MRK 16 antibody and drug accumulation in the presence and absence of PSC 833 for functional P-glycoprotein. Long-term growth in doxorubicin increased the cellular resistance (IC(50)) of K562 cells in a concentration-dependent manner (r(2 )= 0.908). Doxorubicin resistance was not induced in the presence of dexrazoxane (P< 0.0001) for several months. In parallel, the expression of functional P-glycoprotein was delayed after concomitant addition of dexrazoxane to the selecting medium (P< 0.001). Dexrazoxane did not act as a conventional modulator of P-glycoprotein. These results suggest that dexrazoxane may delay the development of MDR1, thus allowing responders to the FAC regime to continue to respond.
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The efficacy of selamectin against adult ascarids was evaluated in eight controlled and masked studies in dogs. Three laboratory studies evaluated selamectin against experimentally induced infections of Toxocara canis; three laboratory studies evaluated selamectin against naturally acquired infections of T. canis; one laboratory study evaluated selamectin against naturally acquired infections of both T. canis and Toxascaris leonina; one field study evaluated selamectin against naturally acquired infections of ascarids (T. canis and/or T. leonina) in dogs presented as veterinary patients. Selamectin was administered topically to the skin of dogs in unit doses designed to deliver a minimum of 6mgkg(-1) (range, 6-12mgkg(-1)). In all studies, dogs were allocated randomly to treatment assignments (selamectin or vehicle control in laboratory studies: selamectin or reference product in the field study) on the basis of pretreatment fecal egg counts. For induced infections, there were significant reductions in geometric mean numbers of adult T. canis after a single application of selamectin (93.9-98.1%, P=0.0001), after two monthly applications (> or =88.3%, P< or =0.0001), and after three monthly applications (100%, P< or =0.0002). In the natural infection laboratory studies, when selamectin was administered twice at an interval of 30 days, the percentage reductions in geometric mean numbers of adult T. canis at necropsy were 84.6, 91.3, and 97.9%, and when selamectin was administered on days 0, 14, and 30, the percentage reductions were 91.1 and 97.6%. Geometric mean fecal T. canis egg counts were reduced by > or =92.9% (P< or =0.0067) at the end of the studies. In the field study, geometric mean fecal ascarid egg counts were reduced by 89.5 and 95. 5% (P=0.0001) for 14 and 30 days, respectively, after a single treatment with selamectin, and by 94.0% (P=0.0001) 30 days after the second treatment with selamectin. These reductions compared favorably with the egg count reductions from dogs treated with a reference product containing praziquantel, pyrantel embonate, and febantel. There were no adverse drug experiences or treatment-related mortalities during any of the studies. Selamectin, when administered topically in a unit dose providing a minimum dosage of 6mgkg(-1), was safe and effective against adult T. canis and T. leonina and in reducing the fecal excretion of T. canis eggs in dogs.
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The bisdioxopiperazine dexrazoxane (ICRF-187) has proven to be clinically very effective in reducing the cardiotoxicity of doxorubicin and other anthracyclines. Doxorubicin is thought to exert its toxicity through iron-based oxygen free radical-induced oxidative stress on the relatively unprotected cardiac muscle. Upon hydrolysis, dexrazoxane forms a compound similar to ethylenediaminetetraacetic acid (EDTA) which, like EDTA, is a strong chelator of iron. Dexrazoxane presumably exerts its cardioprotective effects by either binding free or loosely bound iron, or iron complexed to doxorubicin, thus preventing or reducing site-specific oxygen radical production that damages cellular components. The chemistry, biochemistry, and cell biology of dexrazoxane and other bisdioxopiperazines are discussed. The pre-clinical studies demonstrating the protective effects of dexrazoxane against toxicities caused by doxorubicin, other anthracyclines, bleomycin, alloxan, acetaminophen, and oxygen are also discussed. In vitro and in vivo studies of the cardioprotective and other effects of other bisdioxopiperazines are also covered. Also discussed are the anti-metastatic and radiosensitization effects of razoxane and dexrazoxane. The current clinical status of dexrazoxane in preventing anthracycline-induced toxicities in both adult and pediatric patients is reviewed.
Dexrazoxane prevents the dose-limiting cardiotoxicity of the anthracyclines without reducing their antitumor efficacy and without new adverse side effects. Dexrazoxane reduces the severity of gastrointestinal symptoms of the anthracycline containing combination doxorubicin, 5-fluorouracil, cyclophosphamide and most surprisingly and importantly, dexrazoxane increases the median survival time of advanced breast cancer responders to the doxorubicin, 5-fluorouracil, cyclophosphamide regimen. The median survival time is doubled as compared to controls to nearly 3 years.
The dose-limiting toxicity of the widely used anticancer agent, doxorubicin, is a destructive, irreversible and progressive cardiomyopathy. Prevention of this cardiotoxicity without reduction of antitumour efficacy or the production of new toxicities has therefore been a long-time therapeutic goal. It has now been largely achieved by prior administration of dexrazoxane (DXRz; Cardioxane in Europe; Zinecard in North America; ICRF 187). Six randomized, controlled clinical trials in breast and lung cancer and in soft tissue sarcomas of children have shown a 90% reduction in doxorubicin-induced cardiotoxicity. The results of all these trials lead to the conclusion that DXRz permits: (1) cardiotoxic doses of doxorubicin to be given without cardiotoxicity; (2) patients with increased cardiac risk factors to be treated with full doses of dioxorubicin; (3) second-line treatment with other cardiotoxic drugs.
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High dose dexamethasone combined with irradiation to the base of the brain achieved a dramatic beneficial effect in two terminal cases of widespread metastatic carcinoma of the prostate involving cranial nerves and the entire skeleton. Pain requiring very large doses of analgesics and anemia requiring blood transfusions every 3-4 weeks were improved rapidly. No further transfusions were needed.
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Twenty-five patients with liver metastases, chiefly due to colorectal cancer, were given a loading dose of razoxane for 3 days before 5 consecutive days of radiotherapy to the whole liver. Patients also took razoxane during the radiotherapy and then for one month afterwards. Liver tumour volume was measured on CT scans using the ELSCINT 3D soft tissue imaging programme just before and 4 weeks after the end of radiotherapy treatment. Twelve of the 25 patients had tumour volume reductions of more than 50%. The overall major response rate therefore is 12/25 (48%). In two of the major responders the liver metastases were due to recurrent stomach cancer. In addition to the 12 responders, four patients had a reduction of more than 20% but less than 50%, thus giving an overall response rate of 16/25 (64%). These results can form the basis of a formal, randomized, controlled clinical trial of radiotherapy alone (or any other treatment) compared with radiotherapy and razoxane in the difficult and life threatening condition presented by liver metastases.
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