Inhibition of Mac-1 (CD11b/CD18) enhances tumor response to radiation by reducing myeloid cell recruitment

Despite recent advances in radiotherapy, loco-regional failures are still the leading cause of death in many cancer patients. We have previously reported that bone marrow-derived CD11b⁺ myeloid cells are recruited to tumors grown in irradiated tissues, thereby restoring the vasculature and tumor growth. In this study, we examined whether neutralizing CD11b monoclonal antibodies could inhibit the recruitment of myeloid cells into irradiated tumors and inhibit their regrowth. We observed a significant enhancement of antitumor response to radiation in squamous cell carcinoma xenografts in mice when CD11b antibodies are administered systemically. Histological examination of tumors revealed that CD11b antibodies reduced infiltration of myeloid cells expressing S100A8 and matrix metalloproteinase-9. CD11b antibodies further inhibited bone marrow-derived cell adhesion and transmigration to C166 endothelial cell monolayers and chemotactic stimuli, respectively, to levels comparable to those from CD11b knockout or CD18 hypomorphic mice. Given the clinical availability of humanized CD18 antibodies, we tested two murine tumor models in CD18 hypomorphic or CD11b knockout mice and found that tumors were more sensitive to irradiation when grown in CD18 hypomorphic mice but not in CD11b knockout mice. When CD18 hypomorphism was partially rescued by reconstitution with the wild-type bone marrow, the resistance of the tumors to irradiation was restored. Our study thus supports the rationale of using clinically available Mac-1 (CD11b/CD18) antibodies as an adjuvant therapy to radiotherapy.     

Reoxygenation in the RIF-1 tumor after chemotherapy.

The proportion of hypoxic cells in the RIF-1 tumor was observed for 24 hr after treatments with bleomycin, cisplatin, cyclophosphamide, and mitomycin C. The assays were based upon the paired survival curve method for determining the hypoxic fraction using irradiation of aerobic and artificially hypoxic tumors. It was observed that at 1/2 hr after bleomycin, hypoxic fraction was elevated but returned to baseline levels by 2 hr. Following cisplatin, hypoxic fraction did not rise above baseline. However, after cyclophosphamide, hypoxic fraction was elevated and did not return to baseline over the 24-hr observation period of this study. At 1/2 hr after mitomycin treatment, the hypoxic fraction was raised but within 1 hr returned to baseline. These results indicate that tumor reoxygenation varies after different drug treatments and that the determination of drug specificity for aerobic versus hypoxic cells may be strongly biased by the choice of the time after treatment for making the determination.     

Effect of Chronic Ethanol Exposure on Myocardial Phosphoinositide Turnover

The effect of chronic ethanol consumption (2 months) on atrial contractility and the myocardial phosphoinositide signaling system was examined in rat heart. Two months of ethanol consumption was not associated with changes in heart weight-to-body weight ratios; however, developed twitch tension was significantly lower in the ethanol atria compared with the control atria. Cytosolic and membrane-associated phospholipase C activity in atrial and ventricular tissue was measured and ethanol consumption was only associated with changes in ventricular cytosolic phospholipase C activity. When examining α₁-adrenergic stimulated phosphoinositide turnover in [³H]inositol radiolabeled left atria, no differences in phenylephrine (10 μM)-stimulated inositol monophosphate, inositol bisphosphate, inositol trisphosphate, and inositol tetrakisphosphate were found between groups before or at various times after the addition of phenylephrine. It is concluded that short-term ethanol consumption is associated with depressed contractile function, but not the development of hypertrophy or changes in α₁-adrenoreceptor-stimulated phosphoinositide turnover.     

Long-term Effects of Alcohol Consumption in Male and Female Rats

Discrepancies exist regarding potential sex differences in the effects of ethanol on the myocardium. Therefore, the aims of this study were to determine if long-term ethanol consumption was associated with the development of a dilated cardiomyopathy (CM) in female rats and, second, to determine if the absence of ovarian hormones modulated this effect. Adult male and female (n = 6–8/group) sham-operated and ovariectomized (OVX) Sprague–Dawley rats received the Lieber DeCarli ethanol-containing (8% vol/vol) or control liquid diet for 8 months. All ethanol groups showed echocardiographic evidence of a cardiomyopathy; however, more significant ethanol-elicited differences were found in the male ethanol group than in either the female or female OVX groups. In addition, the male ethanol group had significant reductions in in vivo measures of contractility, such as the maximum derivative of change in systolic pressure and preload recruitable stroke work. Sex differences were also apparent in the pattern and degree of posterior and septal wall thickness changes, in that the male ethanol group had more posterior and septal wall thinning. In conclusion, similar to male rats long-term ethanol consumption in gonad-intact and OVX female rats is associated with the development of a dilated cardiomyopathy.     

Estrogen plus progestin therapy: the cardiovascular risks exceed the benefits

The surprising results of the Women's Health Initiative (WHI) reported in 2002 had a profound effect on women as well as health care practitioners. The WHI was the largest, randomized clinical trial designed to determine if postmenopausal hormone use prevented cardiovascular disease as well as other age-related disorders in women. While observational studies suggested that postmenopausal use of estrogen could decrease cardiovascular risk by 40% to 50%, the WHI demonstrated that use of continuous-combined estrogen plus progestin was not cardioprotective and was even associated with increased health risks. The estrogen alone trial of the WHI is still in progress, leaving practitioners and some women still in a dilemma. This article addresses the WHI in the context of other studies and discusses possible reasons for the unexpected results.     

Effect of blood transfusion in an experimental sarcoma model

OBJECTIVE: To study the effect of allogeneic, syngeneic, and autologous blood transfusion on the growth rate of the KHT tumor in a C3H murine model. DESIGN: Prospective, randomized, and controlled animal study. SUBJECTS: Sixty-one C3H female mice. INTERVENTIONS: The C3H female mice were implanted with 2 x 10(5) cells of KHT, a murine sarcoma. Ten days later, 0.3 mL of blood was removed from a retro-orbital site to simulate surgical blood loss. This blood loss was replaced by blood transfusion through a tail vein with the use of allogeneic (major histocompatibility complex incompatible), syngeneic (major histocompatibility complex compatible), or autologous blood. Tumor growth was measured daily for 14 days. The tumor growth curve for each of the animals was constructed and the mean slope of growth calculated for each group. RESULTS: There were statistically significant differences in tumor growth rate (P =.001) when the allogeneic group (mean slope = 0.232, n = 14), the syngeneic group (mean slope = 0.190, n = 17), and the autologous group (mean slope = 0.202, n = 14) were compared. A t test confirmed that there was no significant difference in the tumor growth rate between the groups transfused with syngeneic and autologous blood (P =.26). However, the rate of tumor growth in the allogeneic group was found to be significantly higher when independently compared with the syngeneic group (P<.001) and the autologous group (P =.02). CONCLUSIONS: In this experimental model of a solid murine sarcoma, allogeneic blood transfusion was associated with an increased rate of tumor growth compared with syngeneic and autologous blood transfusion, likely reflecting immunomodulatory effects incurred by the introduction of major histocompatibility complex-incompatible antigens.     

New blood thinner offers first potential alternative in 50 years: ximelagatran

Traditional anticoagulants employed in the treatment of thrombosis include the injectable heparins and oral warfarin. Though effective, these traditional agents are fraught with limitations in their ease of use in the clinical setting. Warfarin, for example, has many pharmacokinetic properties and food-and-drug interactions that result in unpredictable patient response and the need for expensive and time-consuming monitoring of coagulation status. Ximelagatran is a novel, promising, orally active, direct thrombin inhibitor currently in development that, for the first time in 50 years, offers a potential alternative to the mainstay oral agent "warfarin." Advantages of ximelagatran over warfarin include predictable pharmacokinetics and pharmacodynamics, a broad therapeutic window, no routine anticoagulant monitoring, no clinically significant drug interactions, and fixed-dose administration. Ximelagatran has been evaluated for thromboprophylaxis following orthopedic surgery, acute treatment and secondary prevention of venous thrombosis, stroke prevention in atrial fibrillation, and acute coronary syndromes. Results of clinical trials suggest that ximelagatran is equally or more efficacious than warfarin and/or low-molecular-weight heparin therapy without increasing rates of minor or major bleeding. Although postmarketing surveillance will provide the final test of this drug, the future looks promising for addition of a new anticoagulant with the potential to provide excellent efficacy, predictable response, and reduced adverse effects. Pending regulatory approval, ximelagatran may help overcome barriers to appropriate anticoagulant therapy, thereby decreasing morbidity and mortality associated with thrombotic diseases.