Adriamycin toxicity

Adriamycin toxicity in CBA mice bearing TLX5 lymphoma was reduced by a pharmacological dose of melatonin (20-40 mg/kg) without decreasing the antitumour action of adriamycin (Rapozzi et al. 1998). 

Antineoplastic Drugs. Cyclophosphamide (193) produces antineoplastic effects (see Chemotherapeutics, anticancer) via biochemical conversion to a highly reactive phosphoramide mustard (194) it is chiral owing to the tetrahedral phosphoms atom. The therapeutic index of the (3)-(-)-cyclophosphamide [50-18-0] (193) is twice that of the (+)-enantiomer due to increased antitumor activity the enantiomers are equally toxic (139). The effectiveness of the DNA intercalator dmgs adriamycin [57-22-7] (195) and daunomycin [20830-81-3] (196) is affected by changes in stereochemistry within the aglycon portions of these compounds. Inversion of the carbohydrate C-1 stereocenter provides compounds without activity. The carbohydrate C-4 epimer of adriamycin, epimbicin [56420-45-2] is as potent as its parent molecule, but is significandy less toxic (139). 

Cumulative organ toxicity also presents a significant obstacle for effective chemotherapy. In many cases, the severity of the toxicity impedes the broader use of an agent. Other specific toxicities are associated with specific agents, for example cardiotoxicity with adriamycin (32), renal toxicity with i7j -platinum (28), and neurotoxicity with vincristine (49). 

Pritsos, C.A., Sokoloff, M. and Gustafton, D.L. (1992). PZ-51 (Ebselen) in vivo protection against adriamycin-induced mouse cardiac and hepatic lipid peroxidation and toxicity. Biochem. Pharmacol. 44, 839-841. 

Doxorubicin (Adriamycin) Myelosuppression, alopecia, cumulative dose-limiting toxicity, myocardium damage Given in combination with vincristine and dexamethasone (VAD)... 

The DNA forms stable complexes with doxorubicin (Adriamycin, ADR) and daunorubicin (DNR). Doxorubicin and DNR, although structurally similar, show distinctly different properties ADR is more toxic and active than DNR in the treatment of various human solid tumors the apparent binding affinity of ADR to DNA is about 1.8 times higher than that of DNR to DNA. Trouet et al. [229] found the ADR-DNA complex to be more active than ADR, DNR, or DNR-DNA in subcutaneously inoculated leukemic mice, whereas the DNR-DNA complex showed the highest... 

The use of triphenylethylene SERMs as Pgp inhibitors for clinical application has been hampered by unacceptable toxicity at doses required to achieve adequate cellular concentration, which is likely due to the involvement of proteins with the ability to bind these compounds. For instance, toremifene is able to reverse MDR and to sensitize human renal cancer cells to vinblastine in vitro. However, in vivo toremifene is tightly bound to serum proteins, in particular a 1-acid glycoprotein (AAG), which may limit its tissue availability (Braybrooke et al. 2000). In agreement with this, Chatterjee and Harris (1990) have shown that tamoxifen and 4-OH-tamoxifen were similarly potent in reversing MDR in Chinese hamster ovary (CHO) cells with acquired resistance to adriamycin. However, the addition of AAG (0.5 to 2 mg/ml, the range found in vivo) to cell cultures decreased the effect of tamoxifen on reversing MDR, and at the highest AAG concentration there was a complete reversal of the effects of... 

A new cuithracycllne, aclacinomycin A (Fig. 9) which we discovered in 1976 (28), has been proved by clinical study to be indispensable in the treatment of leukemia. It exhibits a therapeutic effect against leukemia and lymphoma, even against cases resistant to treatment with daunonycin and adriamycin. Dantchev et al. (8) proved that aclacinonycin A has markedly a lower cardiac toxicity in hamsters than does adriamycin. This low cardiac toxicity has also been confirmed by clinical study. 

Anthracyclines are antitumor quinone containing antibiotics produced by different strains of Streptomyces. Some of them, such as adriamycin doxorubicin), and daunorubicin are broad spectrum antitumor compounds. They act by binding to DNA and interfering with DNA replication and gene transcription. Their limitations for clinical use are cardiac toxicity and drug resistance phenomena. Consequently, intense structure-activity relationship studies have been performed to improve the pharmacological profile as well as to enhance the affinity for DNA. In particular, a number of fluorinated anthracyclines have been prepared with introduction of fluorine atoms into D or A cycles, and into the aglycone side chain linked atC-14. ... 

Kinder et al. (123,124) utilized a similar approach to the illudins, more specifically to illudin analogs such as 241 that retain efficacy against various cell lines, but are less toxic. The analog design involves a spirocyclopropyl cyclohexane that contains two electrophilic moieties (Scheme 4.63). Some of the analogs formed are as active as adriamycin against several human tumor cell lines. 

---