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Abstract

The ability of the vitamin E (RRR-A-tocopherol) derivatives A-tocopheryl succinate (A-TOS) and A-tocopheryloxyacetic acid (A-TEA) to suppress tumor growth in preclinical animal models has recently led to increased interest in their potential use for treating human cancer. To make the use of these vitamin E analogues more clinically relevant, we compared the antitumor efficacy of orally and i.p. delivered forms of A-TEA and A-TOS against a murine mammary cancer (4T1) that bears resemblance to human breast cancer because of its poor immunogenicity and high metastatic potential. In cell culture studies, we showed that both compounds inhibited tumor colony formation and induced apoptotic death of tumor cells. To avoid solubility concerns associated with the hydrophobicity of A-TEA and A-TOS, we used the vesiculated forms of A-TEA (VA-TEA) and A-TOS (VA-TOS) for the in vivo tumor studies. Both compounds inhibited the growth of preestablished 4T1 tumors when given i.p. However, when given by oral gavage, only the esterase-resistant VA-TEA was able to suppress primary tumor growth and reduce lung metastasis. To make this approach more translatable to the clinic, A-TEA was incorporated into the diet and fed to tumor-bearing mice. We report here for the first time that dietary A-TEA delivery significantly inhibited primary tumor growth and dramatically reduced spontaneous metastatic spread to the lung in prophylactic and therapeutic settings. This study suggests that dietary A-TEA could prove useful as a relatively easy and effective modality for treating metastatic breast cancer.

We have utilized a free-solution/isoelectric focusing technique (FS-IEF) to obtain fractions rich in multiple chaperone proteins from clarified A20 tumor lysates. Vaccines prepared from chaperone-rich fractions are capable of providing protective immunity in mice subsequently challenged intravenously with the same A20 B cell leukemia cells. This protection is at least equal to that provided by purified, tumor-derived heat-shock protein 70, which was the best chaperone immunogen in our hands against this aggressive murine leukemia model. Dosage escalation studies, however, revealed that increasing vaccine dosages actually abrogated the protective effects. The physical nature of the enriched chaperones indicates that they are associated in complexes, which may have implications for their function. FS-IEF is relatively simple, rapid, and efficient, thus making combined multi-chaperone therapy feasible.