Ketotifen reverses MDR1-mediated multidrug resistance in human breast cancer cells in vitro and alleviates cardiotoxicity induced by doxorubicin in vivo

PURPOSE: To investigate the effect of the antihistamine ketotifen on multidrug resistance in human breast cancer cells and doxorubicin toxicity in mice. METHODS: Clonogenicity assays were used to test the effect of ketotifen on human multidrug resistant breast cancer cell lines exposed to chemotherapeutic agents. Flow cytometry was used to measure accumulation of doxorubicin in cells. Fluorimetry was used to measure accumulation of doxorubicin in cardiac tissues. Histological analysis and toxicity studies in mice were used to test the effect of ketotifen on doxorubicin-induced toxicity. RESULTS: Ketotifen was found to restore the sensitivity of P-glycoprotein-overexpressing multidrug-resistant MCF-7/adr cells to doxorubicin, mitoxantrone, VP-16 and vinblastine, but not to methotrexate or camptothecin. Ketotifen, however, was unable to restore sensitivity of BCRP-overexpressing MCF-7/mx cells or MRP-overexpressing MCF-7/vp cells to mitoxantrone or VP-16, respectively. In vivo, pretreatment of mice with ketotifen caused an increased accumulation of doxorubicin in cardiac tissue, consistent with a block in drug clearance. However, unlike verapamil, ketotifen pretreatment did not enhance doxorubicin toxicity but in fact provided protection, both at the level of cardiac tissue damage and in terms of survival. CONCLUSIONS: Taken together, these observations show that ketotifen is unique in its ability both to reverse multidrug resistance due to P-glycoprotein overexpression and to provide cardioprotection to doxorubicin.     

Bronchioloalveolar carcinoma: a review

The radiographs of 136 patients with bronchioloalveolar carcinoma were reviewed. The varied radiographic manifestations were a result of the characteristic peripheral location of the tumor, its tendency to infiltrate the local airways with mucus production and desmoplasia, and its variable aggressiveness resulting in a wide variation in rate of intrathoracic and extrathoracic spread. In the absence of surgical intervention, a localized lesion progressed to diffuse disease in every patient. The findings supported the concept of bronchioloalveolar carcinoma as a distinct clinical entity.     

Transferrin saturation, plasma iron turnover, and transferrin uptake in normal humans

The relationship between plasma iron, transferrin saturation, and plasma iron turnover was studied in 53 normal subjects whose transferrin saturation varied between 17% and 57%, in 25 normal subjects whose transferrin saturation was increased by iron infusion to between 67% and 100%, and in five subjects with early untreated idiopathic hemochromatosis whose transferrin saturation was continually elevated to between 61% and 86%. The plasma iron turnover of all of these subjects ranged from 0.45 to 1.22 mg/dL whole blood/d. The mean values for the above-mentioned three groups were 0.71 +/- 0.17, 1.01 +/- 0.11, and 1.01 +/- 0.13 mg/dL whole blood/d, respectively. Most of this variation, estimated at 72% by regression analysis, was due to a direct relationship between transferrin saturation and plasma iron turnover. This effect was attributed to a competitive advantage of diferric over monoferric transferrin in delivering iron to tissues. This was confirmed by the demonstration of a more rapid clearance of diferric as compared to monoferric transferrin in an additional group of eight normal subjects. Calculations were made of the amount of transferrin reacting with membrane receptors per unit time. Allowance was made for the noncellular (extravascular) exchange and for the 4.2:1 preference of diferric over monoferric transferrin demonstrated in vitro. The amount of iron-bearing transferrin leaving the plasma to bind to tissue receptors for 53 subjects with a transferrin saturation between 17% and 57% was 71 +/- 13; for 25 subjects with a saturation from 67% to 100%, 72 +/- 12; and for five subjects with early idiopathic hemochromatosis, 82 +/- 11 mumol/L whole blood/d. There were no significant differences among these groups. These studies indicate that while the number of iron atoms delivered to the tissues increases with increasing plasma iron and transferrin saturation, the number of iron-bearing transferrin molecules that leave the plasma per unit time to bind to tissue receptors is relatively constant and within the limits studied, independent of transferrin saturation.     

Chronic osteomyelitis examined by CT

CT examination of 25 patients who had acute exacerbations of chronic osteomyelitis allowed for the correct identification of single or multiple sequestra in 14 surgical patients. Plain radiographs were equivocal for sequestra in seven of these patients, because the sequestra were too small or because diffuse bony sclerosis was present. CT also demonstrated a foreign body and five soft tissue abscesses not suspected on the basis of plain radiographs. CT studies, which helped guide the operative approach, were also useful in treating those patients whose plain radiographs were positive for sequestra. We review the potential role of CT in evaluating patients with chronic osteomyelitis.     

Bronchoalveolar lavage: radiographic manifestations

Bronchoalveolar lavage (BAL) is a safe and well-tolerated procedure in which the lower respiratory tract is sampled through infusion and subsequent aspiration of sterile saline solution. To determine the radiographic changes consequent to this procedure, 25 patients undergoing fiberoptic bronchoscopy and BAL were evaluated prospectively. After lavage, anteroposterior radiographs were obtained immediately and after 30, 90, and 240 minutes, and 24 hours. The degree and site of opacification on the radiographs was graded on a 4+ subjective scale. Sixty-nine lobes were lavaged, but owing to overlap on the radiographs, 52 projected areas were evaluable for radiographic changes. Forty-seven areas of consolidation were identified on the radiographs obtained immediately after lavage. Consolidation was homogeneous and always corresponded to a projected site of lavage. There was a positive correlation between initial opacity on the radiograph and the volume of retained fluid (rs = .60, P less than .001). Consolidation cleared gradually over 24 hours. No patient had clinical pneumonitis. These benign, self-limited radiographic changes are common after BAL and may simulate pulmonary edema, aspiration, or hemorrhage.     

Popliteal cysts and deep venous thrombosis: Tc-99m red blood cell venography

Thirty-four patients who clinically were suspected of having deep venous thrombosis (DVT) underwent Tc-99m red blood cell (RBC) venography followed by contrast venography. The sensitivity (88%) and specificity (94%) of Tc-99m RBC venography for DVT confirmed findings of previous studies. Twenty-four patients who had proved popliteal cysts and swollen calves also were examined using Tc-99m RBC venography. Large cysts (greater than 9 X 4 X 4 cm) showed lack of DVT features, photon deficient cold areas in the popliteal fossa, and diversion of venous flow around the photon deficient area. These features were seen in 25% of the study population (six patients), and assisted in the distinction between the two conditions.