The nursery rhyme "Little Miss Muffet sat on a tuffet (small stool) eating her curds and whey. ..." is recognition of the fact that over the centuries "curds and whey", the two major components of cow's milk, have been widely accepted as part of a healthy diet. Milk provides complete nourishment for the neonate for six months from birth, containing factors that help develop various organ systems including the brain, immune system, and the intestine. Importantly it provides immune protection at a time when the neonates own immune system, though fully developed, is albeit immature. Many adult consumers include cow's milk as part of a healthy diet as it provides protein and essential nutrients, vitamins, and minerals, in particular calcium for strong bones. There is a growing appreciation that milk, and in particular whey, contains components that not only provide nutrition, but can also prevent and attenuate disease, or augment conventional therapies, when delivered in amounts that exceed normal dietary intakes. This paper reviews the emerging health properties of whey proteins and their clinical implications.

Bovine lactoferrin (bLf), an iron-containing natural defence protein found in bodily secretions, has been reported to inhibit carcinogenesis and the growth of tumours. Here, we investigated whether natural bLf and iron-saturated forms of bLf differ in their ability to augment cancer chemotherapy. bLf was supplemented into the diet of C57BL/6 mice that were subsequently challenged subcutaneously with tumour cells, and treated by chemotherapy. Chemotherapy eradicated large (0.6 cm diameter) EL-4 lymphomas in mice that had been fed iron-saturated bLf (here designated Lf + ) for 6 weeks prior to chemotherapy, but surprisingly not in mice that were fed lesser iron-saturated forms of bLf, including apo-bLf (4% iron saturated), natural bLf (B15% iron saturated) and 50% iron-saturated bLf. Lf + -fed mice bearing either EL-4, Lewis lung carcinoma or B16 melanoma tumours completely rejected their tumours within 3 weeks following a single injection of either paclitaxel, doxorubicin, epirubicin or flurouracil, whereas mice fed the control diet were resistant to chemotherapy. Lf + had to be fed to mice for more than 2 weeks prior to chemotherapy to be wholly effective in eradicating tumours from all mice, suggesting that it acts as a competence factor. It significantly reduced tumour vascularity and blood flow, and increased antitumour cytotoxicity, tumour apoptosis and the infiltration of tumours by leukocytes. Lf + bound to the intestinal epithelium and was preferentially taken up within Peyer's patches. It increased the production of Th1 and Th2 cytokines within the intestine and tumour, including TNF, IFN-c, as well as nitric oxide that have been reported to sensitize tumours to chemotherapy. Importantly, it restored both red and white peripheral blood cell numbers depleted by chemotherapy, potentially fortifying the mice against cancer. In summary, bLf is a potent natural adjuvant and fortifying agent for augmenting cancer chemotherapy, but needs to be saturated with iron to be effective.

Intratumoral injection of plasmids that block survivin expression and stimulate the generation of tumor-specific CTLs may be beneficial for the treatment of large lymphomas.

Members of the B7 family costimulate the proliferation of lymphocytes during the initiation and maintenance of antigen-specific humoral and cell-mediated immune responses. While B7-1 and -2 are restricted to lymphoid tissues, and activate naïve T cells, recently identified members including B7-H2 and -H3 are widely expressed on nonlymphoid tissues, and regulate effector lymphocytes in the periphery. B7-H3 has properties that suggested it may display antitumor activity, including the ability to stimulate Th1 and cytotoxic T-cell responses. Here, we test this notion by determining whether intratumoral injection of an expression plasmid encoding a newly described mouse homologue of B7-H3 is able to eradicate EL-4 lymphomas. Intratumoral injection of a mouse B7-H3 pcDNA3 expression plasmid led to complete regression of 50% tumors, or otherwise significantly slowed tumor growth. Mice whose tumors completely regressed resisted a challenge with parental tumor cells, indicating systemic immunity had been generated. B7-H3-mediated antitumor immunity was mediated by CD8 + T and NK cells, with no apparent contribution from CD4 + T cells. In summary, the results indicate that B7-H3 interactions may play a role in regulating cell-mediated immune responses against cancer, and that B7-H3 is a potential therapeutic tool.

Patients with estrogen receptor-positive (ER+) breast cancers are often treated with aromatase inhibitors or by antiestrogens such as tamoxifen to prevent disease recurrence. Resistant tumors nevertheless develop and it is commonly assumed that they arise by the induction of mutations. However, it is also possible that resistant tumors grow from preexisting variant populations within the original tumor. We have investigated this possibility in the case of the MCF-7 breast cancer cell line. The line was cultured for a prolonged period either in the presence of tamoxifen to block the action of oestrogen or in the absence of estrogen to mimic the action of oophorectomy or treatment with aromatase inhibitors. Both treatments led to growth inhibition followed by eventual outgrowth of sub-lines. Five of these sub-lines were developed and characterized for sensitivity to tamoxifen and to the antibiotic rapamycin, expression of HE R2 and PAX2, and phosphorylation of Akt, p70S6K, 4E-BP1, rpS6, EGFR1, Erk and HE R2. All six lines were ER+ and could be divided into four phenotypes distinguished by cell volume, DNA content (ploidy) and cell cycle time. In two cases, selection with tamoxifen and selection in the absence of estrogen produced similar phenotypes. Rapamycin resistance was a feature of the sub-lines developed under estrogen deprivation and was associated with loss of active phospho-HE R2 and acquisition of PAX2 expression. The results support the conclusion that the MCF-7 cell line is heterogeneous and that the selection conditions allow the growth of pre-existing phenotypes.