Immunochemotherapy of a Murine Thymoma with the Use of Idarubicin Monoclonal Antibody Conjugates (original) (raw)
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Cancer research, 1991
Many of the experimental approaches used in the search for new targeted drug delivery systems ignore the disseminated nature of metastatic disease; the development of more relevant tumor models is therefore a priority. A reproducible and tumor-specific model has been generated by inoculating (C57BL/6 x BALB/c) F1 (Ly-2.2+) mice i.v. with the Ly-2.1+ murine ITT(1) 75NS E3 thymic lymphoma (E3). At a dose of 2 x 10(6) cells, E3 tumors grew in a disseminated fashion, arising initially and predominantly in the lung and kidney, and later and less often in the thymus, spleen, and other tissues. In addition, histopathological examination and flow cytometry of blood did not detect E3 tumor cells in most other organs or in the circulation throughout the course of disease. The mean survival time (MST) of untreated mice was both reproducible and proportional to the number of E3 tumor cells injected and was therefore used to demonstrate the suitability of this model for immunochemotherapeutic st...
British Journal of Haematology, 2002
Evaluating the potential benefit of the new anthracycline, idarubicin (Ida), in lymphoma, 58 tumour samples from patients suffering from low-grade non-Hodgkin's lymphoma (L-NHL), were analysed in vitro for their sensitivity to 0AE5 lg/ml Ida. This was compared with the sensitivity to other anthracyclines (0AE5 lg/ml), using the fluorometric microculture cytotoxicity assay. A total of 132 samples from patients with acute leukaemia and a cell-line panel representing different resistance mechanisms was included for comparison. The median cell survival of L-NHL cells did not differ after exposing the cells to Ida or daunorubicin (Dnr), whereas epirubicin, doxorubicin (Dox) and mitoxantrone (Mitox) were significantly less cytotoxic than Ida (P < 0AE001). The median cell survival in L-NHL cells did not differ from that of acute leukaemia cells after exposure to 0AE5 lg/ml Ida, Dnr, Dox and Mitox. Cells from previously treated patients with L-NHL had a higher median survival than cells from untreated patients after exposure to all drugs, except for Ida. In samples from previously untreated patients, Spearman rank correlations were high (Rho ¼ 0AE81-0AE90) between cell survival after exposure to Ida and the other anthracyclines. The same pattern was observed in the cell-line panel (Rho ¼ 0AE78-0AE91) (P < 0AE05). In contrast, low correlations (Rho ¼ 0AE24-0AE42) were observed among samples from previously treated patients. Our results indicate a potential benefit of Ida in previously drug-treated patients with L-NHL.
Idarubicin (4-demethoxydaunorubicin)
Investigational New Drugs, 1986
4-Demethoxydaunorubicin (4-DMDR, IMI 30, Idarubicin, NSC 256439) is a new analog of daunorubicin (DNR) with antileukemic activity in experimental systems that is superior to that of daunorubicin (DNR) or doxorubicin (DX). The drug is more potent than DNR and DX and is active by both the intravenous and the oral routes of administration. After i.v. and oral administration in humans, Idarubicin is rapidly metabolized to its 13-dihydroderivative (Idarubicinol) and the plasma levels of this metabolite are consistently higher than those of the unchanged drug. Idarubicinol has been shown to be an active metabolite in experimental models, being as potent and as active as the parent compound. Phase II clinical trials of Idarubicin have indicated that: By L V. route 1, Idarubicin is a potent antileukemic agent active in relapsed or refractory ANLL, ALL (adult and pediatric) either as single agent or in combination with Ara-C at doses of 8-12 mg/m 2 by i.v. day 1, 2 and 3 or 7-8 mg/m 2 i.v. daily x 5 days (adults). 2. There is evidence of lack of cross-resistance with parent drugs and other antileukemic agents. Phase III studies in previously untreated acute leukemias have been initiated. By oral route 1. Idarubicin has antitumor activity in breast cancer at the doses of 35-45 mg/m 2 q 3-4 weeks or 15 mg/m 2 daily x Tdays q 3-4 weeks. 2. Idarubicin has activity as a single agent in adult leukemias at the do*ses of 20-30 mg/mVday x 3 days. The safety of administration (no risk of extravasation), the good tolerability and the reduced potential for cardiac toxicity, make oral Idarubicin particular attractive for further clinical development. Whether Idarubicin proves to be more effective and/or less cardiotoxic in clinical therapy than DNR or DX remains to be seen through prospective randomized studies which have been already initiated both in leukemias and solid tumors.
Immunology and Cell Biology, 1993
Tumour cell heterogeneity is probably a principal cause of treatment failure and represents a formidable barrier for effective antibody-targeted chemotherapy. Idarubiciti (Ida), a more potent and less cardiotoxic analogue of daunomycin, has been demonstrated to specifically target and eradicate homogeneous, cloned, murine tumour cell populations in vitro and in vivo when coupled to monoclonal antibodies (MoAb); however, the antitumour activity of Ida-MoAb conjugates against human tumour xenografts remains to be established. In this study, the value of cotargeting conjugates to different human tumour-associated antigens within a solid tumour has been assessed by comparing the effects of combinations of Ida-anti-colon carcinoma MoAb conjugates with any one Ida-anticolon carcinoma MoAb conjugate used alone. Individual Ida-MoAb conjugates have previously been evaluated for tbeir specific binding and cytotoxicity to one of two different buman colon carcinoma xenografts (Colo 205 or LIM2210) in vitro, altbough tbeir efficacy alone or in combination required assessment in vivo. Combinations of the most effective Ida-MoAb conjugates were demonstrated to enable a greater number of complete tumour regressions than tbe most efficacious Ida-MoAb conjugate administered alone in vivo; some combinations inhibited control tumour growth by up to 95%. This study suggests tbat Ida-MoAb conjugates can be effective against subcutaneous buman tumours in nude mice, altbough it is unlikely that any single conjugate will eradicate all the tumour cells in a solid tumour, and the value of 'cocktails' of drug-MoAb conjugates against some xenografts (i.e. LIM2210) appears to be limited.
Altered drug sensitivity in response to idarubicin treatment in K562 human leukaemia cells
British Journal of Haematology, 1999
Relative to the commonly used anthracyclines, little is known about idarubicin and the development of multidrug resistance. We have previously shown the K562/ IDA subline resulting from intermittent treatment of the K562 human leukaemia cell line with 20 ng/ml idarubicin did not develop multidrug resistance but became more sensitive to etoposide. Additional similar treatments of this subline produced the K562/IDA20 subline which partially retained its etoposide sensitivity although these cells expressed P-glycoprotein and were resistant to paclitaxel. Sensitization to etoposide was associated with increased decatenation activity of topoisomerase II, although there were no changes in topoisomerase IIa expression or formation of etoposide-dependent cleavable complexes. In comparison, the K562/IDA10 subline produced by intermittent treatment of the K562 cells, ®rstly with 5 ng/ml then 10 ng/ml idarubicin, showed no detectable expression of P-glycoprotein, decreased topoisomerase IIa expression and increased resistance to etoposide and amsacrine, but not to idarubicin or genistein. Even though intermittent treatment with idarubicin caused increased drug resistance in both sublines, they remained sensitive to idarubicin. Therefore the potential of idarubicin as a substitute for other anthracyclines in the treatment of cancer warrants further investigation.
Phase I study of idarubicin administered orally on a daily � 3 schedule
Investigational New Drugs, 1990
Twenty-one adult patients with refractory solid tumors were treated on a phase I study of idarubicin (4-demethoxydaunorubicin) administered daily for 3 days every 3 weeks. Nineteen of the patients had received previous chemotherapy (including 13 with prior anthracyclines), and 12 had received prior radiotherapy. Idarubicin dose levels of 10, 15, 17.5, 20, and 25 mg/m 2 were explored. Hematological toxicity was dose-related. Other toxicity was acceptable. Only one patient (treated with an idarubicin dose of 17.5 mg/m2/day) developed neutropenic fever, from which he recovered. Further dose escalations beyond 25 mg/m 2 were not carried out because of the increasing length of time required for recovery from granulocytopenia at higher doses. No patient experienced a major response, but minor responses were seen in 3 patients with carcinomas of the colon, breast, and kidney respectively. Further phase II studies of oral idarubicin at a Starting dose of 20-25 mg/m 2 daily times 3 days in patients with good bone marrow reserves are recommended. Because of the degree of neutropenia expected, patients would have to be observed carefully.
Idarubicin-bromelain combination sensitizes cancer cells to conventional chemotherapy
Iranian Journal of Basic Medical Sciences, 2019
Objective(s): The primary cytotoxic effects of anticancer drugs like idarubicin, a chemotherapeutic agent, are not limited to neoplastic cells; they also produce similar effects in normal cells. In this study, we hypothesized that the combination of idarubicin-bromelain could make cancer cells more susceptible to cytotoxicity and genotoxicity. Materials and Methods: To test our hypothesis, the optimal concentrations of idarubicin and bromelain were combined and incubated in the HL-60 cancer cell line and normal human mononuclear leukocytes (PBMC) for 24, 48, and 72 hr. Cytotoxicity and genotoxicity were evaluated by measurement of ATP cell viability test, DNA damage, Caspase-3, Acridine orange/ethidium bromide (AO/EB), and DAPI fluorescent dyes in both cell types. Results: The combination of idarubicin-bromelain significantly reduced cell proliferation in the more potent HL-60 compared to PBMC in all incubation times (P<0.05). DNA damage and Caspase-3 levels (except for 24 hr) we...
Immunotargeting of daunomycin to localized and metastatic human colon adenocarcinoma in athymic mice
Cancer Immunology Immunotherapy, 1992
A monoclonal antibody (designated SF25), which recognizes a protein antigen expressed on a large number of human colon carcinomas, was used for drug targeting. Daunomycin-antibody conjugates were prepared by two previously described procedures. In one, the drug was bound to the antibody through a spacer of small molecular mass (cis-aconitic acid), while in the other a dextran bridge served as the link between drug and antibody. High substitution rates of drug to antibody were obtained using the latter binding procedure. Both conjugates were tested in vitro against two human colon carcinoma cell lines, LS 180 and KM-12. The efficacy of a daunomycin-dextran-SF25 antibody conjugate was tested against colon carcinoma LSI80 tumors transplanted at different sites into athymic mice. The specific conjugate was significantly more inhibitory to a subcutaneous tumor growth than its components or their mixture. SF25 antibody alone showed antitumoral effects against all three forms of transplanted tumor tested, namely, local, metastatic or intrahepatic, whereas daunomycin, on its own, was effective only against the subcutaneous tumor. Binding of daunomycin to dextran partially improved its inhibitory activity against the metastatic tumor. The conjugate, daunomycin-dextran-SF25 antibody reduced the number of metastatic foci, increased the survival rate and delayed death. Yet against lymph node metastases it was not significantly better than a mixture of both constituents. However, results obtained with an intrahepatic tumor, a model that mimics the natural progression of the disease, resembled those described with the subcutaneous tumor. Daunomycin-dextran-SF25 antibody was significantly more effective than all components separately and than a mixture of drug and antibody, provided a highly drug-substituted conjugate was used.
Oral Idarubicin in the Treatment of Advanced Breast Cancer
Acta Oncologica, 1989
Idarubicin (IDA), a more lipophilic derivative of daunorubicin, has shown activity after oral administration. In November 1983 we initiated a phase I1 study administering IDA, 45 mg/m', in a 3 weekly schedule as first line chemotherapy to postmenopausal women with advanced breast cancer. Among 50 eligible patients a response rate of 36% (95% confidence interval (CI): 23-51) was obtained. Median time to treatment failure was 22 weeks (95 % CI: 15-32). In November 1986, a sequential phase I1 study with IDA given in a weekly schedule was initiated. Patient characteristics was comparable to the first study. Among 53 evaluable patients, the response rate was 34% (95% CI: 22-48), and rnedian time to treatment failure was 19 weeks (95% CI: 13-33). Therapeutic efficacy in the two studies was comparable and similar to published data on doxorubicin. Hematologic toxicity was equal while non-hematologic toxicity was considerably lower in the weekly schedule. A phase 111 comparison of IDA to doxorubicin or epi-doxorubicin is warranted, in order to clarify the role of IDA in the treatment of advanced breast cancer.
Antineoplastic activity of idazoxan hydrochloride
Cancer Chemotherapy and Pharmacology, 2009
Purpose Idazoxan hydrochloride (IDA) is a 241 molecular weight imidazoline and adrenoreceptor ligand. It binds to mitochondrial membranes and promotes apoptosis of pancreatic beta cells. Since IDA has not been tested against tumor cells, the purpose of our study was to determine if IDA has antineoplastic activity. Methods We used the conversion of a soluble tetrazolium salt to an insoluble formazan precipitate and diVerential staining cytotoxicity assays to determine if IDA was cytotoxic to cell lines of murine lung cancer and human prostate cancer, as well as to a variety of fresh human tumor samples. We used Xow cytometry to analyze cell death and calreticulin expression. Results IDA is cytotoxic to both cell lines and against aliquots of specimens of breast, gastric, lung, ovarian and prostate cancers as well as non-Hodgkin's lymphoma. It produces apoptotic cell death and promotes calreticulin expression, suggesting that IDA might be immunomodulatory in vivo. Conclusion We anticipate that IDA will be clinically useful in cancer treatment.