Clin Cancer Res
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Clinical Trial
Phase I clinical and plasma and cellular pharmacological study of topotecan without and with granulocyte colony-stimulating factor.
Topotecan, a semisynthetic water-soluble analogue of camptothecin, inhibits human topoisomerase I (topo I). We performed a Phase I clinical and plasma pharmacological study of topotecan administered by 24-h continuous infusion without and with granulocyte colony-stimulating factor (G-CSF). We also measured topo I-DNA complexes in peripheral blood mononuclear cells (PBMCs) in an attempt to correlate formation of topo I-DNA complexes in patients treated with topotecan with toxicity and/or response. ⋯ The mean increase in topo I-DNA complexes at the end of the topotecan infusion was 1.25 times the pretreatment value. There was a statistically significant relationship (P = 0.02) between lack of disease progression and the level of topo I-DNA complexes measured in PBMCs before therapy. For Phase II studies of minimally treated adults with solid tumors, the recommended topotecan starting dose administered by 24-h continuous infusion is 10 mg/m2 without G-CSF.
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The goal of this study was to determine whether the serum tumor marker half-life (MHL) of human chorionic gonadotropin (HCG) and alpha-fetoprotein (AFP) during initial chemotherapy can complement pretreatment risk stratification in metastatic nonseminomatous germ cell tumors. One hundred forty-seven patients were assessable for MHL during the first two cycles of platinum-based chemotherapy. MHL calculation was based on two consecutive values using Kohn's apparent half-life formula (MHL =ln 1/2/G, where G was the gradient of the marker slope) or on three (or more) values using simple linear regression. ⋯ The test accuracy was 70% for both progression-free and overall survival, and it was slightly greater than the overall predictive value of the Medical Research Council prognostic classification. A combination of Medical Research Council criteria and MHL analysis allowed us to refine prognostic assessment. Because MHL analysis is able to complement pretreatment risk stratification and can support selection of patients for early-dose intensified chemotherapy, it should be included in prospective clinical trials for patients with poor-prognosis disease.
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We have constructed a fusion protein composed of tumor necrosis factor alpha (TNF-alpha) fused at its COOH terminus to the scFv region of monoclonal antibody (mAb) B1, an antibody that recognizes LeY antigen present on many human cancer cells. Our rationale for fusing the scFv to the COOH terminus of TNF was to diminish the binding of the fusion protein to TNF receptors because the COOH terminus of TNF is involved in binding, and thus to partially inactivate (detoxify) the molecule. The Fv region should then target and accumulate the fusion protein on cancer cells, which should compensate for the reduced binding affinity of the TNF moiety and lead to selective killing of TNF-sensitive antigen-expressing cancer cells. ⋯ TNF-B1(Fv) kills TNF-alpha-sensitive cells that do not express the target antigen only at much higher doses than TNF trimer, and it does not kill LeY-bearing but TNF-alpha-resistant cells. TNF-B1(Fv) can cause significant tumor regression of MCF-7 tumor xenografts in mice at doses that are not toxic to the mice. Thus, the reduced binding of the TNF moiety to TNF receptors, combined with binding of the B1(Fv) portion to LeY antigen, makes TNF-B1(Fv) an agent for selective killing of LeY-expressing TNF-sensitive cancer cells.
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There is experimental and clinical evidence that angiogenesis is involved in breast cancer progression and metastasis. To investigate whether the determination of angiogenesis adds prognostic information to the estrogen receptor (ER) status, we studied a series of 178 node-positive breast cancer patients, with a median follow-up time exceeding 5 years, treated with adjuvant tamoxifen (TAM). We assessed angiogenesis by the quantification of the intratumoral microvessel density and the determination of the Chalkley score using light microscopy. ⋯ We found that angiogenesis adds significant prognostic information to ER status in predicting the outcome of breast cancer patients treated with adjuvant TAM. In fact, irrespective of the ER status, the patients with highly angiogenic tumors had a poor outcome, even if treated with TAM. For these patients, the inhibition of angiogenesis with specific angioinhibitory drugs may be a promising new therapeutic strategy.
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Bizelesin (U-77779, NSC 615291), a synthetic analogue of the cytotoxic antibiotic CC-1065, is a bifunctional alkylating agent that produces DNA interstrand cross-links. Bizelesin was evaluated for antitumor activity against a broad spectrum of syngeneic murine tumors and human tumor xenografts in mice. Systemic drug administration produced >6.7 log10 cell kill against i.p. implanted P388 and L1210 leukemias and 80% tumor-free survivors against s.c. implanted L1210. ⋯ The complete cross-resistance of the doxorubicin-resistant subline to bizelesin suggests that bizelesin may be a substrate for the efflux pump that causes multidrug resistance. Due to its breadth of antitumor activity, potency, unique mechanism of action, and lack of cross-resistance with other alkylating agents, bizelesin was selected for development in clinical trials by the National Cancer Institute and the Upjohn Company. Toxicological studies and pharmaceutical development have been completed, and clinical trials are planned to start in the summer of 1996.