Possible mechanisms for the agonist actions of tamoxifen and the antagonist actions of MER-25 (ethamoxytriphetol) in the mouse uterus

Experiments were conducted to determine why tamoxifen, a non-steroidal antiestrogen, is uterotrophic in mice, whereas MER-25 (ethamoxytriphetol), a structurally related compound, is antiuterotrophic. Initial experiments indicated that the pituitary was not required for a uterotrophic response in mice to either estradiol (E2), tamoxifen (TAM), or 4-hydroxytamoxifen (4-OH-TAM) MER-25 was not uterotrophic in mice but was capable of completely inhibiting the uterotrophic responses of mice to estrogens (E2) as well as antiestrogens (TAM and 4-OH-TAM); this inhibition was reversible by increasing the dose of the antiestrogen (TAM). The relative binding affinities (RBA) of TAM, 4-OH-TAM, and MER-25 to mouse uterus estrogen receptor (ER) and mouse liver antiestrogen binding sites (AEBS) were compared to determine whether either (or both) of these sites mediate the biological effects of these compounds. E2 is arbitrarily assigned an RBA of 100 for ER; similarly, TAM is assigned an RBA of 100 for AEBS. MER-25 bound to AEBS with an RBA of 8.9 and to ER with an RBA of less than 0.06; in contrast, TAM and 4-OH-TAM bound to AEBS with RBAs of 100 and 53, respectively, and to ER with RBAs of 2 and 131, respectively. Five other compounds that had similar RBAs as MER-25 for AEBs (RBAs in the range 4-9) and for ER (RBAs less than 0.06) were tested for their antiuterotrophic activities in vivo against both estrogen (E2) and antiestrogen (TAM) in ovariectomized mice. None of these compounds were antiuterotrophic against either estradiol or tamoxifen (P less than 0.01), nor were any of the compounds uterotrophic in mice. These data suggest that differences in the biological actions of tamoxifen and MER-25 in mice are not mediated through AEBS and are most likely due to differences in their interactions with ER.     

Obesity and body fat distribution and breast cancer prognosis

This study addresses the effect of obesity and body fat distribution on axillary lymph node involvement, tumor size, and estrogen receptor (ER) level in breast cancer patients. Anthropometric measurements were prospectively obtained on 248 consecutively and newly diagnosed women with invasive breast cancer. The anthropometric measurements evaluated were abdomen, thigh, subscapular, and midaxillary skinfolds; weight; and height. Weight and Quetelet Index (kg/m2) were significantly (P = 0.001) associated with lymph node involvement in postmenopausal patients. The abdomen:thigh skinfold ratio was significantly higher in premenopausal patients (P = 0.004) and postmenopausal (P = 0.03) without axillary node involvement compared with women with 4+ axillary node involvement. The abdomen:thigh skinfold was higher (P = 0.05) in women with smaller breast cancers (less than 2.0 cm) and higher ER levels. Weight and Quetelet Index did not affect tumor size or ER level. This study demonstrated that obese postmenopausal women who developed breast cancer tend to have more axillary node involvement than their leaner counterparts. Generalized obesity did not affect tumor size or ER level. Premenopausal and postmenopausal women with upper body fat distribution appear to be a subset of women who have a more favorable prognosis as measured by less lymph node involvement, smaller tumors, and higher levels of ER in their tumors.     

Dose intensity and hematologic toxicity in older breast cancer patients receiving systemic chemotherapy

BACKGROUND:

This prospective study evaluated patient and treatment characteristics that contributed to hematologic toxicity in older breast cancer patients treated with curative intent in the community setting.

METHODS:

Data were collected on 1224 patients with stage I through III breast cancer, of whom 207 were aged ≥65 years (grading determined according to the American Joint Committee on Cancer staging system). Primary outcome measures included anemia, thrombocytopenia, severe neutropenia, febrile neutropenia, and both planned and actual relative dose intensity (RDI). Comparisons between older and younger patients regarding hematologic toxicity and reductions in RDI were based on univariate and multivariate logistic regression analyses.

RESULTS:

The neutropenic complication rate in older patients (45.1%) was not significantly different from that in the younger patients (43.7%). There were also no significant differences in rates of anemia or thrombocytopenia. Approximately 34.0% of the older patients received RDI <85% compared with 20.0% among younger patients (P < .01). Fewer older patients received anthracycline‐based chemotherapy (64.3% compared with 83.8% in younger patients, P < .01). Fewer older patients received prophylactic white blood cell colony‐stimulating factor (18.4%) compared with younger patients (28.0%) (P < .01).

Conclusions:

There were no significant differences noted with regard to chemotherapy‐related hematologic toxicities between older and younger breast cancer patients in this large prospective observational study. This may be explained, in part, by more frequent reductions in RDI and less frequent utilization of anthracyclines among older patients. Cancer 2009. © 2009 American Cancer Society.     

Treatment planning study for carcinoma of the esophagus: helium ions versus photons

Helium ion radiotherapy significantly reduces dose to adjoining critical structures in the treatment of carcinoma of the esophagus when the same treatment plan is compared with megavoltage photon therapy. A five-field 18 MV photon treatment plan, selected to minimize lung dose, is compared with helium ions using the same field configuration. Dose volume histograms show target coverage, as well as dose delivered to critical structures lung, heart, mediastinum, and spinal cord. Although both helium ions and photons deliver approximately the same lung dose for this treatment plan, radiation to the heart and spinal cord from this field arrangement is significantly reduced with the helium ion beam. The concentration of dose at the tumor site, while sparing surrounding normal tissue, is characteristic of charged particle therapy, particularly with light ions, which includes particles with Z from that of protons (Z = 1) through that of neon (Z = 10).     

Activity of bleomycin in iron- and copper-deficient cells

Three models were used to examine the requirement of bleomycin (Blm) for iron (Fe) to carry out its antitumor or cytotoxic activity. Mice were made iron deficient by dietary means. Animals with depressed iron stores in liver and low plasma and ascites fluid iron supported Ehrlich tumor growth as well as mice maintained on a control diet. Bleomycin was equally effective against this tumor in iron-deficient mice as it was against the tumor in iron-sufficient controls. Likewise, nutrient copper deficiency did not change the efficacy of the drug. Ehrlich cells in culture were treated with a non-growth inhibiting concentration of the chelating agent, 1,10-phenanthroline before or during their exposure to bleomycin. Again, the treated cells were as sensitive to drug as controls, despite the fact that this ligand reduces cellular iron and zinc and can extract iron from Fe(II)Blm. Lastly, it was demonstrated that iron-depleted Euglena gracilis cells growing at reduced rates were as sensitive to growth inhibition by bleomycin as control cells.