Our Solid Tumor Autologous Marrow Program Project Grant (STAMP) is designed to develop curative treatment for breast cancer, small cell lung cancer and refractory lymphoma. It is derived from the intersection of the paradigms of combination chemotherapy and marrow transplantation. The program has been an integrated basic and clinical science effort and has produced improved survival in metastatic breast and small cell lung cancer. The first project is the conduit for translation of the basic projects to the clinic. We select and apply preclinical leads to the clinic in quantitative experimental designs and parallel laboratory studies. In addition to dose, schedule and combination chemotherapy studies, we give major emphasis to the study of new agents appropriate for STAMP. The second project relates to the pharmacology of the AAs. We find that variability in cyclophosphamide pharmacokinetics has major implications for toxicity and response. We have developed new methodology for the study of cyclophosphamide biotransformation products. These and related studies of ifosfamide and thiotepa are designed to improve the safety and effectiveness of the STAMP program. We have found that cimetidine presumably inhibits detoxification of 40H CPA. Preliminary clinical pharmacokinetic studies show an increased concentration of 40H CPA, which is the activated metabolite, by the addition of cimetidine. The third project involves tumor vaccine development based on the evidence that lack of co-stimulatory factors such as, B-7 in antigen presenting cells, precludes the development of in vivo tumor immunity. The vaccine will consist of a vaccinia virus which contains the B-7 stimulatory gene along with the tumor antigen gene. Phase 1 studies will be performed in stage IV breast cancer patients and definitive studies in patients with microscopic tumor (MRT) (stage I and IIIA). The fourth project includes our minimal residual tumor (MRT) approach. The detection of MRT in patients in complete remission from STAMP has major therapeutic implications. Our preliminary studies, using keratin and other antibodies indicate that with confocol microscopy and immunofluorescence, one tumor cell in a million can be detected. Also, we will evaluate novel targets employing subtractive hybridization and palindrome PCR.
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