aclarubicin and Neoplasm-Metastasis

To determine the efficacy of aclarubicin hydrochloride in local control of malignant pericardial effusion, the authors carried out a trial of pericardial drainage with local administration of this agent in five patients, whose effusions had produced cardiac tamponade. All patients were women, and their primary cancers, all initially treated surgically, had arisen in the breast (two patients), or lung (three patients). Mean patient age was 54.2 years (range, 43-62). In four patients, improvement permitted removal of the drainage catheter. Two patients (40%) had a complete remission of the malignant pericardial effusion. The other three patients were difficult to evaluate because nonpericardial metastases limited their survival. All patients, however, showed disappearance of malignant cells from the pericardial sac with no cytopathologically demonstrable recurrence. In our few patients, intrapericardial aclarubicin appeared to be highly effective against malignant pericardial effusion.

Topics: Aclarubicin; Adult; Antineoplastic Agents; Breast Neoplasms; Cardiac Tamponade; Catheterization; Drainage; Female; Humans; Injections, Intralesional; Lung Neoplasms; Middle Aged; Neoplasm Metastasis; Pericardial Effusion; Treatment Outcome

Aclarubicin is an anthracycline antibiotic that differs from doxorubicin in its structure, mechanism of action, and preclinical toxicity profile, especially its reduced cardiotoxicity. We therefore conducted a side-by-side in vivo and in vitro trial of this agent in metastatic breast-cancer patients and their biopsied tumor specimens, respectively. Aclarubicin (100 mg/m2) was given by intravenous infusion every 3 weeks to 22 patients with objectively measurable metastatic breast cancer, 15 of whom had not previously received doxorubicin. The dose-limiting toxicity consisted primarily of leukopenia and severe nausea and vomiting. No objective response was observed in the 19 evaluable patients. After disease progression, 10 of the 15 doxorubicin-naive patients were treated with doxorubicin; 6 patients achieved a partial response, including 4 who responded to doxorubicin alone and 2 who responded to doxorubicin in combination with thiotepa and vinblastine. Tumor specimens were obtained from 14 of the 22 patients prior to the start of therapy and were tested for in vitro sensitivity to aclarubicin and doxorubicin using a soft agar colony-forming assay. Adequate colony growth occurred in 9 of 14 cultured tumor specimens. All 9 specimens, including 3 obtained from doxorubicin-naive patients, demonstrated in vitro resistance to aclarubicin. In all, 1 of 3 specimens taken from doxorubicin-naive patients demonstrated in vitro sensitivity to doxorubicin, whereas 6 tumor specimens obtained from patients who had undergone prior doxorubicin therapy demonstrated in vitro resistance. The patient whose tumor demonstrated in vitro doxorubicin sensitivity responded to a doxorubicin regimen after failing aclarubicin treatment; in vitro doxorubicin resistance correlated with clinical resistance in all cases. We conclude that aclarubicin is inactive in metastatic breast cancer at the dose and schedule used. Side-by-side in vivo and in vitro trials are feasible and could be useful in the development of investigational agents with activity greater than that of aclarubicin and, particularly, in the evaluation of analogs of clinically active drugs.

Topics: Aclarubicin; Adult; Aged; Breast Neoplasms; Doxorubicin; Drug Resistance; Female; Humans; In Vitro Techniques; Middle Aged; Neoplasm Metastasis; Treatment Outcome; Tumor Stem Cell Assay

Topics: Aclarubicin; Adenocarcinoma; Adult; Aged; Alopecia; Antibiotics, Antineoplastic; Breast Neoplasms; Drug Evaluation; Female; Humans; Middle Aged; Naphthacenes; Nausea; Neoplasm Metastasis; Neutropenia

The acquisition of drug resistance mediated by the interaction of tumor cells with the extracellular matrix (ECM), commonly referred to as cell adhesion-mediated drug resistance (CAM-DR), has been observed not only in hematopoietic tumor cells but also in solid tumor cells. We have previously demonstrated that a 22-mer peptide derived from fibronectin, FNIII14, can inhibit cell adhesion through the inactivation of β1 integrin; when coadministered with cytarabine, FNIII14 completely eradicates acute myelogenous leukemia by suppressing CAM-DR. In this study, we show that our FNIII14 peptide also enhances chemotherapy efficacy in solid tumors. Coadministration of FNIII14 synergistically enhances the cytotoxicity of doxorubicin and aclarubicin in mammary tumor and melanoma cells, respectively. The solid tumor cell chemosensitization induced by FNIII14 is dependent upon the upregulation and activation of the pro-apoptotic protein, Bim. Furthermore, the metastasis of tumor cells derived from ventrally transplanted mammary tumor grafts is suppressed by the coadministration of FNIII14 and doxorubicin. These results suggest that the coadministration of our FNIII14 peptide with chemotherapy could achieve efficient solid tumor eradication by increasing chemosensitivity and decreasing metastasis. The major causes of tumor recurrence are the existence of chemotherapy-resistant primary tumor cells and the establishment of secondary metastatic lesions. As such, coadministering FNIII14 with anti-cancer drugs could provide a promising new approach to improve the prognosis of patients with solid tumors.

Topics: Aclarubicin; Animals; Antineoplastic Agents; Apoptosis; Bcl-2-Like Protein 11; Cell Adhesion; Cell Line, Tumor; Doxorubicin; Drug Resistance, Neoplasm; Drug Synergism; Female; Fibronectins; Humans; Mammary Neoplasms, Experimental; Melanoma, Experimental; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Peptide Fragments

In an attempt to improve the combined effects of hyperthermia and anti-cancer drugs, an intratumorous (i.t.) injection of the drugs was performed and its effect compared with that obtained by intraperitoneal (i.p.) injection. Using Lewis lung carcinoma growing in the legs of BDF1 mice, weakly toxic drug derivatives, Aclarubicin (ACR), a new platinum complex (DWA2114R), or Peplomycin (PEP) were injected either into the center of the tumors, or intraperitoneally, before or after usual hyperthemia in a 43.5-43.7 degrees C water bath for 45 min. The effects on tumor growth delay and the number of lung metastases were assessed, and the enhancement ratios (ERs) due to the combination were calculated. Tumor growth inhibition by i.t. injection was enhanced additively with ACR (ER; 1.2) and synergistically with DWA2114R (ER; 3.49) and PEP (ER; 2.4) plus hyperthermia. Hyperthermia after i.t. injections of DWA2114R (ER; 3.4) was more effective than either i.t. or i.p. injections after hyperthermia (ER; 2.4). Lung metastases were also inhibited significantly by the combination of hyperthermia and drugs, except when emulsified PEP was injected three times. It was concluded that the i.t. injection of DWA2114R was of value when used in combination with hyperthermia.

Topics: Aclarubicin; Animals; Antineoplastic Agents; Carboplatin; Carcinoma, Lewis Lung; Combined Modality Therapy; Disease Models, Animal; Female; Hyperthermia, Induced; Injections, Intralesional; Injections, Intraperitoneal; Male; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Peplomycin

A novel anthracycline antibiotic, siwenmycin, isolated from the culture of Streptomyces galilaeus var. siwenesis, was examined for its antitumor activities against P388, K562, B16-F10, HeLa, HEp-2 and Lewis lung carcinoma cell lines. The results showed that siwenmycin was effective against P388, K562, HeLa and HEp-2 tumor cell lines in vitro, and significantly inhibited the growth of the Lewis lung carcinoma cell line in vivo. Siwenmycin could also suppress spontaneous and artificial pulmonary metastases of B16-F10 and Lewis lung carcinoma cell lines in C57BL/6 mice. The inhibitory effect of siwenmycin on spontaneous pulmonary metastasis of Lewis lung carcinoma in C57BL/6 mice was even stronger than that of adriamycin (ADM), which is, at present, commonly used in clinical practice. Furthermore, the double-labeling test used in this study has verified that siwenmycin can inhibit cellular RNA synthesis at about one tenth the concentration required to inhibit DNA synthesis to the same degree, indicating that the antitumor mechanism of siwenmycin also differs from that of ADM. The acute toxicity of siwenmycin was very low, and it was as effective in vivo as in vitro, suggesting that this newly found antibiotic should be studied for possible clinical antitumor applications.

Topics: Aclarubicin; Animals; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; DNA, Neoplasm; Doxorubicin; HeLa Cells; Humans; Injections, Intraperitoneal; Lung Neoplasms; Melanoma, Experimental; Mice; Mice, Inbred Strains; Mitolactol; Mitomycins; Neoplasm Metastasis; RNA, Neoplasm; Tumor Cells, Cultured

Study on antitumor activity of free and liposomal anthracycline antibiotic aclarubicin in vitro and in vivo showed that liposomal aclarubicin was characterised by activity against ascitic Ehrlich carcinoma comparable to that of free aclarubicin when used in a dose of 25 mg/kg. Liposomal antibiotic had a more pronounced antimetastatic action and showed no toxicity (in a dose of 30 mg/kg). Liposomal aclarubicin had a higher activating capacity with respect to the macrophage tumoricidal properties.

Topics: Aclarubicin; Animals; Carcinoma, Ehrlich Tumor; Drug Carriers; Drug Screening Assays, Antitumor; Emulsions; Lethal Dose 50; Leukemia P388; Liposomes; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Neoplasm Metastasis

Marked antimetastatic activity of aclarubicin, an anthracycline antibiotic, was demonstrated on models of spontaneous and artificial metastases of murine tumors such as Lewis lung carcinoma and melanoma B16. The activity depended on the antibiotic dose and administration regimen. The highest antitumor effect of aclarubicin was observed when the antibiotic was used at the earliest periods after intravenous injection of the tumor cells (the model of artificial metastases) or after amputation of the limb with the tumor (spontaneous metastases). Aclarubicin was active after administration by any of the routes used: intravenous, intraperitoneal and oral, the latter by its efficiency being not inferior to the parenteral administration. When used intravenously aclarubicin showed activity similar to that of adriamycin. However, after oral administration only aclarubicin had antimetastatic action.

Topics: Aclarubicin; Administration, Oral; Animals; Drug Evaluation, Preclinical; Injections, Intraperitoneal; Injections, Intravenous; Lung Neoplasms; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Neoplasm Transplantation; Time Factors

Topics: Aclarubicin; Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Humans; Middle Aged; Naphthacenes; Neoplasm Metastasis

Thirty-two patients with measurable metastatic colorectal cancer refractory to 5-fluorouracil-containing regimens received aclacinomycin A (ACM-A) on a single-dose I.V. schedule administered over 4 hours every 3 weeks. Good-risk patients received ACM-A at the starting daily dose of 100 mg/m2 while patients who had had therapy with radiation or myelosuppressive drugs such as mitomycin C or a nitrosourea compound received an initial daily dose of 80 mg/m2. There were no complete or partial remissions in this study. Twelve of 30 evaluable patients had disease stabilization. Nausea and vomiting were the dose-limiting toxic effects; myelosuppression was moderate, with neutropenia more severe than thrombocytopenia. Other toxic effects included diarrhea (in 53% of the treatment courses), phlebitis (36%), and mucositis (27%). Alopecia was rare and occurred in 3% of treatment courses, while none of the patients developed clinical manifestation of cardiac toxicity. Aclacinomycin-A administered by the single-dose schedule as used in this study is not effective against colorectal cancer.

Topics: Aclarubicin; Adult; Aged; Antibiotics, Antineoplastic; Colonic Neoplasms; Drug Evaluation; Female; Humans; Male; Middle Aged; Naphthacenes; Nausea; Neoplasm Metastasis; Neutropenia; Rectal Neoplasms; Thrombocytopenia

Topics: Aclarubicin; Aged; Antibiotics, Antineoplastic; Drug Eruptions; Female; Humans; Naphthacenes; Neoplasm Metastasis; Stomach Neoplasms