Cancer research
-
The basis for current clinical trials in the treatment of colorectal cancer with the combination of irinotecan (CPT-11) and 5-fluorouracil (FUra) with or without leucovorin (LV) is their proven activity as single agents, their different mechanisms of action, and lack of CPT-11 cross-resistance to previous FUra/LV treatment. The role of drug dose and administration sequence in this combination was studied in vivo using a rat colon tumor model (Ward colon carcinoma); we administered CPT-11 and FUra by i.v. push once a week for four consecutive weeks (weekly x 4), a clinically relevant schedule. The maximum tolerated doses (MTDs) of CPT-11 and FUra administered as single agents were 100 mg/kg/week for both agents. ⋯ With the sequential combination of CPT-11 followed 24 h later by FUra (sequence III), the high complete tumor regression rate (cure) could be maintained, even when the dose of CPT-11 was reduced to 12.5% of the MTD as long as the doses of FUra was kept at 50 -75 % of the MTD. The data demonstrate that the antitumor activity and toxicity of combining CPT-11 with FUra is highly sequence dependent and that a sequence of CPT-11 preceding FUra is superior with a significant increase in the therapeutic index over the other sequences tested. In addition, the data also demonstrate that toxicity associated with high dose of CPT-11 can be eliminated without loss of the antitumor efficacy by reducing the dose of CPT-11 to at least 50% of its MTD, whereas the dose of FUra is kept at 50-75 % of its MTD.
-
Plasma cell neoplasia in humans generally occurs as multiple myeloma, an incurable form of cancer. Tumors with marked similarity can be induced in mice by a variety of agents, including chemicals, silicone, and oncogene-containing retroviruses, suggesting the use of murine tumors as an informative model to study plasma cell disease. Herein, we have focused on the role of insulin-like growth factor I receptor (IGF-IR) signaling in the development of plasma cell disease. ⋯ Biological relevance was demonstrated in that plasma cell lines with up-regulated IGF-IR expression levels exhibited mitogenic responses to IGF-I. More importantly, expression of a dominant-negative mutant of IGF-IR in these lines strongly suppressed tumorigenesis in vivo. Taken together, these results demonstrate that up-regulation and activation of IGF-IR and the downstream signaling pathway involving insulin receptor substrate 2, phosphatidylinositol 3'-kinase, and p70S6K may play an important role in the development of a broad spectrum of plasma cell tumors.