edotecarin and Breast-Neoplasms

The replacement of 1,3-dihydroxy-2-propylamino moiety at the N6-position of edotecarin (1) by arylmethylamino groups yielded a number of more potent topoisomerase I inhibitors with better cytotoxic (CTX) activities in vitro than edotecarin. Among them, the three most potent pyridylmethyl analogues, compounds 22g, 22m, and 23c, showed better antitumor activities against MKN-45 human stomach cancer or MX-1 human breast cancer xenografted mice than those of edotecarin. Furthermore, compounds 22m and 23c exhibited complete response against MX-1 cells implanted in mice.

Topics: Amines; Animals; Antineoplastic Agents; Breast Neoplasms; Carbazoles; Cell Line, Tumor; Enzyme Inhibitors; Female; Humans; Hydrocarbons, Aromatic; Mice; Pyridines; Stomach Neoplasms; Structure-Activity Relationship; Topoisomerase I Inhibitors; Xenograft Model Antitumor Assays

Edotecarin (J-107088, formerly ED-749) is a potent indolocarbazole topoisomerase-I inhibitor that has the potential to treat solid tumors. The current studies evaluated the potency and antitumor activity of edotecarin, as a single agent and in combination with capecitabine or docetaxel.. Antiproliferative activity was tested in vitro in a panel of 13 mammary cell lines and antitumor efficacy was tested in vivo in various breast cancer models.. Edotecarin inhibited cellular proliferation in breast carcinoma cell lines: 50% inhibitory concentrations ranged from 8 nmol/L in SKBR-3 cells to approximately 30 micromol/L in BT20 cells. Single dose and weekly intravenous treatments with edotecarin 30 and 150 mg/kg produced significant antitumor activity in the SKBR-3 human breast carcinoma xenograft model, with no major toxicities, compared with vehicle solvent treatment. Daily administration of edotecarin 15 mg/kg for 10 days was not well tolerated, whereas the total dose of 150 mg/kg was safe when administered in a single injection. Edotecarin 3 and 30 mg/kg given after docetaxel in the nude mouse SKBR-3 xenograft model produced tumor growth delays that were greater than those observed with either agent alone and with no toxicity as evaluated on the basis of body weight reduction (<20%). Furthermore, edotecarin 3 mg/kg in combination with capecitabine produced more than additive effects and the combination was well tolerated. However, edotecarin at a dose of 30 mg/kg in combination with capecitabine was lethal. Edotecarin also exhibited potent antitumor activity against xenografted human MX-1 cells, MMTV-v-Ha-ras oncogene-driven mouse breast tumors, and chemically induced rat mammary tumors.. The data suggest that edotecarin may be useful as a single agent or a component of combination chemotherapy regimens for treating human breast cancer.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carbazoles; Cell Line, Tumor; Cell Proliferation; Docetaxel; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Female; Humans; Indoles; Inhibitory Concentration 50; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Mice, Nude; Rats; Rats, Sprague-Dawley; Taxoids; Topoisomerase I Inhibitors

J-107088 (6-N-(1-hydroxymethyl-2-hydroxy)ethylamino-12,13-dihydro-2,10-dihydroxy- 13-(beta-D-glucopyranosyl)-5H-indolo[2,3-a]-pyrrolo [3,4-c]carbazole-5,7(6H)-dione) is a derivative of NB-506, an indolocarbazole compound previously reported as an anti-tumor agent targeting topoisomerase I. The optimal administration schedule of J-107088 was found to be intermittent injections. The GID75 (75% growth inhibiting total dose) values of J-107088 against LX-1 lung cancer and PC-3 prostate cancer when given by intermittent injection (twice a week for 2 consecutive weeks) were 200 and 15 mg/m2, respectively, whereas the 10% lethal dose (LD10) values of J-107088 against LX-1- and PC-3-bearing mice were 578 and 1200 mg/m2. The ratio of LD10/GID75 indicates the therapeutic window of an anti-tumor agent. Although the ratios of doxorubicin, paclitaxel and cisplatin against PC-3 were <0.3, <0.5 and <0.2, J-107088 showed the widest therapeutic window among the anti-tumor drugs tested. J-107088 was also effective on cells that had acquired resistance related to P-glycoprotein. Furthermore, J-107088 was found to be highly effective in inhibiting proliferation of micro-metastases of tumors to the liver in mice. Therefore, J-107088 is considered to be a promising candidate as an anti-tumor drug for treatment of solid tumors in humans.

Topics: Animals; Antineoplastic Agents; Body Weight; Breast Neoplasms; Carbazoles; Cisplatin; Colonic Neoplasms; Doxorubicin; Drug Administration Schedule; Female; Glucosides; Humans; Indoles; Leukemia P388; Lung Neoplasms; Male; Mice; Mice, Inbred Strains; Mice, Nude; Neoplasms; Paclitaxel; Prostatic Neoplasms; Time Factors