Clin Cancer Res
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We examined the effect of norsegoline, a natural marine product, and dibezine, a synthetic product, on the survival of human myeloid progenitor cells [colony-forming unit-cells (CFU-C)] from normal individuals and from 10 patients with Philadelphia-positive chronic myelogenous leukemia (CML) in chronic phase and blastic crisis. We compared their effect to the effect of IFN-alpha. Norsegoline, dibezine, and IFN-alpha inhibited the proliferation of CFU-C in a dose-dependent manner. ⋯ BCR/ABL translocations were detected in 94.6 +/- 0.6% of cells following their growth in liquid culture for 7 days. Following exposure of CD34(+) cells to norsegoline, dibezine, or IFN-alpha, BCR/ABL fusion signals could be detected in 73 +/- 11%, 66.5 +/- 4. 7%, and 66.0 +/- 2.5% of cells from BM and 72.3 +/- 5%, 68.8 +/- 7%, and 60.6 +/- 6.8% of peripheral blood, respectively. Our data indicate that norsegoline and dibezine have in vitro an antileukemic effect against Philadelphia-positive cells and may be used in conjunction with currently available agents for ex vivo purging of BM and/or peripheral blood of CML patients in conjunction with autologous bone marrow transplantation.
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Comparative Study
Preclinical antitumor efficacy of the polyamine analogue N1, N11-diethylnorspermine administered by multiple injection or continuous infusion.
Certain N-alkylated analogues of the natural polyamine spermine have been found to disrupt polyamine pool homeostasis and inhibit tumor cell growth. The most effective of these analogues, N1, N11-diethylnorspermine (DENSPM), apparently depletes intracellular polyamine pools primarily by inducing the polyamine acetylating enzyme spermidine/spermine N1-acetyltransferase, which contributes to polyamine depletion via increased polyamine excretion and catabolism. In this report, the experimental therapeutic efficacy of DENSPM was further examined with the use of other human solid tumor xenografts, including A121 ovarian carcinoma, A549 lung adenocarcinoma, HT29 colon carcinoma, and SH-1 melanoma, and compared with previously obtained findings with MALME-3M and PANUT-3 human melanomas. ⋯ The rapidly growing human LOX melanoma xenograft, however, demonstrated poor induction of N1-acetyltransferase activity and the poorest response to DENSPM treatment. In nude athymic mice with MALME-3M melanoma xenografts, constant infusion delivery of DENSPM resulted in prolonged inhibition of tumor growth and long-term tumor regressions comparable to those produced by multiple i.p. injections. On the basis of the unique structure of DENSPM, novel target and mode of intervention, mild host toxicity, and activity against different human solid tumor xenografts, DENSPM is currently being developed as an antitumor agent in humans.
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Pharmacokinetic studies that consisted of measuring the plasma drug profile, tissue drug distribution, and elimination in urine and feces were performed in female C57BL/6 x DBA/2 (hereafter called B6D2F1) and male B6D2F1A/2 and C57BL/6 x CH3 (hereafter called B6C3F1) mice following treatment with a 1-h i.v. infusion of the PZA, PD115934 (NSC 366140). This drug is the first of a new class of cytotoxic agents and was selected for clinical trials because of both its broad antitumor activity in vivo against murine solid tumors and human xenografts, and its in vivo toxicity profile that was predictable based on drug dose and schedule of administration. The pharmacokinetic results obtained here in mice have been used to facilitate the dose escalations during the Phase I trial and to determine pharmacokinetic drug exposure targets for its acute and sub-acute toxic effects. ⋯ Urinary excretion was higher (range, 5-28% of the dose administered) and did show evidence of sex-related differences, with male urinary drug excretion being higher than female urinary drug excretion. The drug was >/=95% protein bound. Preliminary evidence for drug metabolism was found in urine and feces and will be further explored.