Does caloric restriction extend life in wild mice?

To investigate whether mice genetically unaltered by many generations of laboratory selection exhibit similar hormonal and demographic responses to caloric restriction (CR) as laboratory rodents, we performed CR on cohorts of genetically heterogeneous male mice which were grandoffspring of wild-caught ancestors. Although hormonal changes, specifically an increase in corticosterone and decrease in testosterone, mimicked those seen in laboratory-adapted rodents, we found no difference in mean longevity between ad libitum (AL) and CR dietary groups, although a maximum likelihood fitted Gompertz mortality model indicated a significantly shallower slope and higher intercept for the CR group. This result was due to higher mortality in CR animals early in life, but lower mortality late in life. A subset of animals may have exhibited the standard demographic response to CR in that the longest-lived 8.1% of our animals were all from the CR group. Despite the lack of a robust mean longevity difference between groups, we did note a strong anticancer effect of CR as seen in laboratory rodents. Three plausible interpretations of our results are the following: (1) animals not selected under laboratory conditions do not show the typical CR effect; (2) because wild-derived animals eat less when fed AL, our restriction regime was too severe to see the CR effect; or (3) there is genetic variation for the CR effect in wild populations; variants that respond to CR with extended life are inadvertently selected for under conditions of laboratory domestication.

Spatial accuracy of fractionated IMRT delivery studies in canine paraspinal irradiation.

Intensity modulated radiation therapy (IMRT) theoretically allows detailed tailoring of the dose distribution in tissue. The goal of this study was to determine if a method of dynamic IMRT could be used to deliver a high dose of radiation to a concave shaped target around the cervical spinal cord. Fifteen young adult dogs from our laboratory population were randomly divided into two groups. A radiation dose of 84 Gy in 4 Gy fractions was delivered with a conventional 4 field technique for Group A dogs, and with dynamic IMRT for Group B dogs to a "C-shaped" target close to the cervical spinal cord. Neurologic status, magnetic resonance imaging results and histopathologic changes were compared among dogs in the two groups. Group A dogs developed myelomalacia with a latency period of 65 +/- 9 days. Group B dogs did not have any histologic changes to the cervical spinal cord when euthanasia was performed 12 months after irradiation. The results demonstrate that this IMRT technique can be safely and precisely delivered to a patient in a clinical situation.

p53 expression, growth, and spontaneous metastasis of the human GI 101 breast carcinoma in athymic nude mice.

The human GI 101 breast carcinoma cell lines produces spontaneous metastasis to the lungs when xenografted subcutaneously in female athymic nude mice. To establish the time-course of tumor growth and distant metastasis to the lungs and axillary lymph nodes, 5 mm3 of tumor tissue was implanted in the subaxial region of female athymic nude mice. Micrometastases in the lung were first detected 3 weeks after tumor implantation. The incidence of lung metastasis and the number of tumor emboli were correlated with the volume of the primary tumors. Ipsilateral axillary lymph node metastasis was observed within 17 weeks, indicating that metastasis to the lymph node is a later event. Unlike pulmonary micrometastases which were in the form of clusters of four to six tumor cells, metastasis to the lymph nodes were in nodules of poorly differentiated and larger tumor cells. Immunohistochemistry evaluation of p53 oncoprotein in the primary and metastatic tumor cells showed different patterns of subcellular accumulation. Cytoplasmic staining was mainly detected in the primary and secondary tumor cells disseminated to the lungs. In contrast, nuclear staining was only detected in tumor cells infiltrated to the axillary lymph nodes. There was no gain of loss of positivity of p53 accumulation (i.e., qualitative measurements) as the tumor grew in size. The data indicate that the GI 101 tumor cells could be used as a useful model for studying the malignant progression of hormone-independent breast cancer, antimetastatic drugs, and early events in tumor metastasis.