pirarubicin and Cardiomyopathies

Doxorubicin is an essential component of the treatment of aggressive lymphoma, childhood solid tumors, bone and soft tissue sarcomas, and breast cancer and additional indications are emerging. On the other hand, daunorubicin has occupied the central position of interest in the treatment of acute leukemia. Epirubicin has a spectrum very similar to doxorubicin but lesser toxicity. The ability to protect against cardiotoxicity with ICRF-187 further enhances clinical interest in exploiting modifications in doze intensity to therapeutic advantage. Idarubicin has at least equivalent activity to daunorubicin and doxorubicin in leukemia. New areas of research in relation to anthracycline antibiotics include introduction of new the analogs, insight into mechanisms of resistance, the reversal of multidrug resistance in vitro, the protection of cardiac toxicity, and the study of other important biochemical reactions relevant to cytotoxicity. Orally active anthracyclines such as idarubicin and compounds which lack cross-resistance with the parent drugs or have other mechanisms for cytotoxicity are being developed. It is likely that these modifications will lead to an expanding therapeutic spectrum for these already widely useful drugs.

Topics: Aclarubicin; Antibiotics, Antineoplastic; Cardiomyopathies; Carubicin; Doxorubicin; Drug Resistance; Epirubicin; Humans; Idarubicin; Menogaril; Molecular Structure; Neoplasms; Nogalamycin

Doxorubicin is an essential component of the treatment of aggressive lymphoma, childhood solid tumors, bone and soft tissue sarcomas, and breast cancer and additional indications are emerging. On the other hand, daunorubicin has occupied the central position of interest in the treatment of acute leukemia. Epirubicin has a spectrum very similar to doxorubicin but lesser toxicity. The ability to protect against cardiotoxicity with ICRF-187 further enhances clinical interest in exploiting modifications in doze intensity to therapeutic advantage. Idarubicin has at least equivalent activity to daunorubicin and doxorubicin in leukemia. New areas of research in relation to anthracycline antibiotics include introduction of new the analogs, insight into mechanisms of resistance, the reversal of multidrug resistance in vitro, the protection of cardiac toxicity, and the study of other important biochemical reactions relevant to cytotoxicity. Orally active anthracyclines such as idarubicin and compounds which lack cross-resistance with the parent drugs or have other mechanisms for cytotoxicity are being developed. It is likely that these modifications will lead to an expanding therapeutic spectrum for these already widely useful drugs.

Topics: Aclarubicin; Antibiotics, Antineoplastic; Cardiomyopathies; Carubicin; Doxorubicin; Drug Resistance; Epirubicin; Humans; Idarubicin; Menogaril; Molecular Structure; Neoplasms; Nogalamycin

Pirarubicin (THP) is an anthracycline frequently used in the chemotherapy against acute leukemia, malignant lymphoma and several solid tumors. However, its clinical use is severely limited by the development of a progressive dose-dependent cardiomyopathy that results in irreversible congestive heart failure. To provide a strategy for constraining or minimizing the cumulative cardiotoxicity of THP, a pirarubicin liposome powder (L-THP) was appropriately prepared, and the cumulative cardiotoxicity of L-THP and free THP (F-THP) were investigated on Sprague-Dawley rats after 3 successive doses. Urinary samples for metabonomic study, serum samples for biochemical assay, and heart samples for histopathology test were collected. As a result, the metabonomics-based findings such as PLS-DA plotting showed minimal metabolic alterations in L-THP as compared to F-THP, and correlated with the changes of serum biochemical assay and cardiac histopathology as measurements of damage to heart tissue. Our results confirm that when encapsulated into liposomes, the cumulative cardiotoxicity of THP can be greatly ameliorated. Lipophilic aglycone metabolites of THP associated with redox cycling are cardiotoxic for the possibility of reactive oxygen species (ROS) formation. Also, metabonomic analysis shows that the successive doses of THP will lead to severe metabolic pathways disturbances in the cell energy production. Further, the preliminary efficacy study of L-THP on lung cancer was evaluated in the approach of in vitro cytotoxicity on A549 cells by high content screening (HCS) analysis, and L-THP was found to exhibit better therapeutic index against lung cancer than THP.

Topics: Animals; Antibiotics, Antineoplastic; Biotransformation; Cardiomyopathies; Cell Line, Tumor; Cell Survival; Doxorubicin; Heart Failure; Histocytochemistry; Liposomes; Male; Metabolomics; Myocardium; Powders; Rats; Rats, Sprague-Dawley

In a previous study, we demonstrated that apoptosis in rats with adriamycin (ADR)-induced cardiomyopathy occurred through a Fas-dependent pathway. Pirarubicin, a new anthracycline derivative, seems to have a lower cardiotoxicity than ADR. To investigate whether pirarubicin has a lower chronic cardiotoxicity compared with ADR, ADR or pirarubicin were injected weekly for 8 wk into young Wister rats via the tail vein. To block the Fas-Fas ligand interaction, an anti-Fas ligand antibody (FasL) was injected with ADR 7, 8, and 9 wk after first administration of ADR. In the control group, saline was injected instead of ADR. ADR significantly induced apoptosis and left ventricular dysfunction 10 wk after the first administration of ADR. Pirarubicin also induced apoptosis, however, its apoptosis was significantly (p = 0.0069) less than that induced by ADR. Fas antigen was overexpressed in the hearts of ADR and ADR+FasL groups, however, an expression of Fas antigen in the pirarubicin group was similar to the expression of Fas antigen in the control group. Thus, pirarubicin has a significantly lower chronic cardiotoxicity compared with ADR.

Topics: Animals; Antibiotics, Antineoplastic; Apoptosis; Cardiomyopathies; Doxorubicin; Fas Ligand Protein; fas Receptor; Heart; In Situ Nick-End Labeling; Male; Membrane Glycoproteins; Myocardium; Rats; Rats, Wistar

A 25 year-old woman diagnosed as acute myelocytic leukemia (M0) suffered a fourth relapse in February 1992 at which time she already had anthracycline-induced cardiac dysfunction. Although remission was induced by low dose cytosine arabinoside and etoposide combined with pirarubicin, she developed acute heart failure followed by extreme elevation of transaminases level and DIC. Abdominal echography and CT revealed small round lesions in the liver. We diagnosed this episode as ischemic hepatitis because of the following clinical findings; serological markers of virus hepatitis were negative, hypotension and reduced blood flow to the liver were seen, and both transaminases and LDH were markedly elevated. Dobutamin and oxygen inhalation were started, her liver function returned to almost normal levels 8 days later.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Cardiomyopathies; Cytarabine; Doxorubicin; Etoposide; Female; Hepatitis; Humans; Ischemia; Leukemia, Myeloid, Acute; Liver; Remission Induction