Doxorubicin plus interleukin-2 chemoimmunotherapy against breast cancer in mice.

As recently characterized, following s.c. implantation into syngeneic C57BL/6 mice, E0771 tumor invades locally into dermal layers and peritoneum, metastasizes to the lung, and induces a nonspecific immunosuppression in the host. Using this breast medullar adenocarcinoma model, a therapy consisting of a single moderate dose of doxorubicin followed by twice daily moderate doses of interleukin-2 for 30 days was examined for efficacy and mechanism of action when given to animals with established disease. This combination treatment, but not combinants alone, resulted in tumor-free long-term survival of 40% of the mice without significant toxicity and 83% of survivors had immune memory specific for E0771 cells. Treatment also decreased immune suppression induced by E0771 tumor. Full response to treatment required functional CD8(+) T cells, whereas depletion of natural killer cells caused only a reduction in response rate. A serum "biomarker" profile that correlated with, and seemed predictive of, response to treatment was identified by nuclear magnetic resonance-based metabonomic analysis. The efficacy of this nontoxic treatment and the potential to be able to predict which individual is responding to treatment are characteristics that make this chemoimmunotherapy attractive for clinical testing.

Distant metastasis from subcutaneously grown E0771 medullary breast adenocarcinoma.

BACKGROUND: Breast cancer treatments are most effective when initiated early, with very poor efficacy against metastatic disease. In seeking a readily metastasizing mouse breast cancer model to facilitate the search for effective therapies, E0771 medullary adenocarcinomas implanted subcutaneously in syngeneic C57BL/6 mice were studied. MATERIALS AND METHODS: Standard pathological, histological and immunological methodologies were used. RESULTS: The aggressive estrogen receptor-positive tumor invaded locally into the peritoneal cavity in 56% of mice, as well as metastasizing to the lungs in 52% of mice. The metastasis was a spontaneous event and immunosuppression was seen (e.g. generation of lyphokine activated killer cells and allogeneic cytotoxic T lymphocytes cytolytic activities ex vivo were suppressed). Other pathological events noted as the tumor progressed were: bloody ascites (56%) and shock (72%), both attributed to local (peritoneal) tumor invasion. CONCLUSION: The E0771 metastatic breast cancer model, which mimics the human disease, should be useful in testing new treatments against this disease and/or in examining the metastatic process.

Fluorouracil plus leucovorin induces submandibular salivary gland enlargement in rats.

The administration of 5-fluorouracil (FU) and leucovorin (LV) to rats induced a previously unreported sialoadenitis-like toxicity. Four different treatment regimens were used: daily-times-5 iv or ip injections of LV (200 mg/kg) followed 30 minutes later by FU (27.5 mg/kg or 35 mg/kg). These treatments resulted in 3 severity levels of systemic toxicity indicated by changes in body weight. In addition to the well known FU+LV-induced diarrhea, myelosuppression, and stomatitis, facial edema, and enlargement of the submandibular salivary gland were consistently seen. Facial edema occurred almost exclusively in rats that subsequently underwent excessive weight loss and were euthanized. The submandibular, but not parotid or sublingual, salivary gland was enlarged and the severity of this effect changed in a bell-shaped relationship with respect to increasing FU+LV induced loss of body weight. Histologic examination of affected glands established the occurrence of bacterial infection, sialoadenitis and destruction of gland tissue. This paper provides the first known documentation of FU+LV treatment-induced selective pathology of the submandibular salivary gland. The selectivity of this toxicity, apparently not normally seen in humans, to the submandibular salivary gland of the rat is of interest and its mechanism warrants further investigation.

Immunomodulation in cancer therapeutics.

Clinical verification is being obtained, with a variety of different therapeutic approaches, for the concept that anticancer treatments based on exploiting the host's own antitumor defense mechanism can be beneficial. Nevertheless, as was seen with both chemotherapeutic and radiation treatments, the benefit of single agent treatments is not great. It is anticipated that, in attempting to realize the maximal potential of anticancer treatments based on exploiting the host's own antitumor defense mechanism, it will be necessary to utilize combination therapies. For medical-ethical reasons, the ability to effectively combine such treatments with ones with proven clinical efficacy should increase the enthusiasm for the initiation of clinical trials. Chemotherapeutic agents may serve this purpose, since, contrary to the generally held tenet that anticancer chemotherapeutic agents are merely immunosuppressive, there is considerable literature describing their ability to augment antitumor host defenses. This review attempts to collate this information derived by numerous investigators employing diverse experimental approaches with a number of the most widely used anticancer chemotherapeutic agents.

Doxorubicin induces specific immune functions and cytokine expression in peritoneal cells.

To examine the basis of the immune modulation induced by the anticancer agent doxorubicin (DOX), the immunophenotype, tumoricidal activity, cytokine protein and mRNA expression were determined using peritoneal exudate cells (PEC) from saline-treated (untreated) and DOX-treated mice. A greater percentage of PEC from DOX-treated mice than from untreated mice were adherent to plastic, had characteristics of granulocytes, and were positive for the NK1.1, CD11b/Mac-1, and CD3 markers. DOX decreased the percentage of CD45R/B220+ cells. PEC from DOX-treated mice had greater tumoricidal potential than those from untreated mice since IL2, LPS, or IFNgamma alone increased the cytolytic activity of PEC from DOX-treated mice, whereas PEC from untreated mice required both LPS and IFNgamma to become cytolytic. DOX treatment modulated the expression of specific cytokines. Following stimulation in culture, PEC from DOX-treated mice produced more TNF, IL1, and IFNgamma than PEC from untreated mice. DOX treatment increased the levels of TNF, but not IL1, mRNA and decreased the levels of IL6 mRNA and protein. These data demonstrate that a single DOX injection induces specific effects in PEC and, as a consequence, increases the tumoricidal potential of cells of the macrophage and natural killer types.