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  • cloning assay  (2)
  • 1
    ISSN: 1573-0646
    Keywords: anthracyclines ; cloning assay ; morpholino anthracyclines ; MX2
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In several preclinical systems, the morpholino anthracycline MX2 has greater antitumor activity than doxorubicin, is less cardiotoxic, and is effective against multidrug resistant cancer cells. We used a human tumor soft-agar cloning assay to test the cytotoxicity of MX2 against single cell suspensions from freshly obtained human tumors. Tumor cells were exposed to MX2 at 0.05 and 0.5 μg/ml either for 1 hour (201 specimens; 77 [38%] assessable) or continuously (231 specimens; 91 [39%] assessable). Superior antitumor activity was observed with continuous exposure (19%in vitro response at 0.05 μg/ml and 69% at 0.5 μg/ml) than with 1-hour exposure (1.3% at 0.05 μg/ml and 12% at 0.5 μg/ml). Activity was seen against all types of cancer tested including renal (91%), melanoma (88%), ovarian (73%), breast (71%) and non-small-cell lung (67%) cancer at a MX2 concentration of 0.5 μg/ml after continuous exposure. If appropriate plasma levels can be achieved in patients, MX2 could have significant clinical activity in patients with those tumors.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1569-8041
    Keywords: cloning assay ; ecteinascidins ; minor groove binding agents ; tetrahydroisoquinolone alkaloids
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: Ecteinascidin-743 (ET-743), a member of the ecteinascidin family selected for clinical development, is a tetrahydroisoquinolone alkaloid isolated from the marine ascidian, Ecteinascidia turbinata. This novel compound is a minor groove binding, guanine-specific alkylating agent which also interacts with the microtubule network and blocks cell cycle progression at late S/G2. Materials and methods: A soft agar cloning assay was used to determine the in vitro effects of ET-743 against primary human tumor specimens taken directly from patients. A total of 93 evaluable specimens were exposed to ET-743 for one-hour (n = 25) and/or 14-day continuous exposure (n = 92) at concentrations ranging from 0.1 nM to 1 µM. In vitro responses were defined as an inhibition ≥50% of human tumor colony forming units at a given concentration. Results: One-hour exposure to ET-743 at concentrations of 0.1 nM, 1 nM, 10 nM, 100 nM and 1 µM induced in vitro responses in 0% (0/17), 6% (1/17), 16% (4/25), 13% (1/8), and 25% (2/8) of specimens, respectively. Continuous exposure to ET-743 at concentrations of 0.1 nM, 1 nM, 10 nM, 100 nM and 1 µM, inhibited 0% (0/16), 13% (2/16), 49% (44/90), 62% (47/76), and 77% (58/75) of tumor specimens, respectively. Tumor-specific responses and concentration-dependent relationships were observed with a continuous exposure to ET-743. At 100 nM, the compound inhibited 79% (11/14) breast, 69% (9/13) non-small-cell lung, 58% (7/12) ovary, and 88% (7/8) melanoma specimens. At 1 µM, ET-743 inhibited 100% (14/14) breast specimens, 85% (11/13) non-small-cell lung, 67% (8/12) ovary and 86% (6/7) melanoma specimens. Activity of ET-743 at and above 10 nM was also observed against sarcoma and kidney tumors. At 10 nM concentration and continuous exposure ET-743 demonstrated incomplete cross-resistance with paclitaxel, alkylating agents, doxorubicin and cisplatin. Conclusions: Our data from the cloning assay indicate that the duration of exposure to ET-743 is an important factor in human tumors. Therefore, long-term exposure to ET-743 may be preferred in future clinical trials. The activity of ET-743 in breast, non-small-cell lung, and ovarian cancers as well as in melanoma may deserve further clinical evaluations. The potential of ET-743 in sarcoma and renal tumors might also be considered. In addition, our data indicate that a plasma concentration of 100 nM of ET-743 must be considered as a target during the clinical development of the compound; also the concept of continuous/protracted exposure in clinical trials with ET-743 has to be taken into account.
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