Doxorubicin sarcomas

Andronova, N.V, Bokhyan, B.Yu., Nikolaev, A.L., Treschahna, E.M., Aliev, M.D., Kovalevskiy, E.E., Filonenko, D.V, Gopin, A.V., Bozhevolnov, V.E., Kogan, B.Ya., Vorozhtsov, G.N. Rationale for clinical study of preoperative treatment of soft hssue sarcomas with local ultrasound hyperthermia and chemotherapy with cisplatin and/or doxorubicin. Sarcoma of bone, soft tissue and skin tumors, 2011, 1, 28-33 (in Russian). 

Liposomal doxorubicin is an irritant, not a vesicant, and is dosed differently from doxorubicin, so clinicians need to be very careful when prescribing these two drugs. The pharmacokinetics of liposomal doxorubicin are best described by a two-compartment model, with a terminal half-life of 30 to 90 hours.20 Liposomal doxorubicin has shown significant activity in the treatment of breast and ovarian cancer, along with multiple myeloma and Kaposi s sarcoma. Side effects include mucositis, myelosuppression, alopecia, and palmar-plantar erythrodysesthesia. The liposomal doxorubicin may be less cardiotoxic than doxorubicin. 

The delivery of doxorubicin to the SI80 sarcoma (tumor) in mice, using niosomes as a carrier, has been studied by Rogerson [168]. Much higher tumor drug levels were reported with niosomes prepared using the nonionic surfactant I and 50% cholesterol than with free... 

Widder KJ, Morris RM, Poore GA, Howard DP, Senyei AE (1983b) Selective targeting of magnetic albumin microspheres containing low-dose doxorubicin total remission in Yoshida sarcoma-bearing rats. Eur J Cancer Clin Oncol 19 135-139. 

Cheung TW, Remick SC, Azarnia N, Proper JA, Barrueco JR, Dezube BJ. AIDS-related Kaposi s sarcoma a phase II study of liposomal doxorubicin. The TLC D-99 Study Group. Clin Cancer Res 1999 5 3432. 

Coukell AJ, Spencer CM. Polyethylene glycol-liposomal doxorubicin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the management of AIDS-related Kaposi s sarcoma. Drugs 1997 53 520. 

Grunaug M, Bogner JR, Loch O, Goebel FD. Liposomal doxorubicin in pulmonary Kaposi s sarcoma improved survival as compared to patients without liposomal doxorubicin. Eur J Med Res 1998 3 13. 

Judson I, Radford JA, Harris M, et al. Randomised phase II trial of pegylated liposomal doxorubicin (DOXIL(R)/CAELYX(R)) versus doxorubicin in the treatment of advanced or metastatic soft tissue sarcoma, a study by the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 2001 37 870. 

Northfelt DW, Dezube BJ, Thommes JA, et al. Pegylated-liposomal doxorubicin versus doxorubicin, bleomycin, and vincristine in the treatment of AIDS-related Kaposi s sarcoma results of a randomized phase III clinical trial. J Clin Oncol 1998 16 2445. 

In September 2007, the EMEA approved the use of trabectidin against ovarian cancer (OC) and STS. In November 2009, Yondelis received its second marketing authorization from the European Commission for its administration in combination with pegylated liposomal doxorubicin (Doxil, Caelyx) for the treatment of women with relapsed ovarian cancer presently, trabectedin (36) is under Phase II trials for the treatment of paediatric sarcomas as well as breast and prostate cancers. The European Commission and the US Food and Drug Administration (FDA) have granted orphan drug status to trabectedin for soft tissue sarcomas and... 

There are three liposomal forms of doxorubicin or daunorubicin on the market (Table 8.6). Doxil and DaunoXome have been approved for the treatment of AIDS-related Kaposi s sarcoma and are being evaluated in clinical trials for the treatment of a variety of cancers [148-151]. Evacet (liposomal doxorubicin) has recently been tested in large phase II and III clinical trials for the treatment of metastatic breast cancer and is awaiting approval by the FDA [151], Data obtained from trials thus far suggest that all three liposomal drugs offer significant therapeutic benefit compared with the free drug [113]. 

Doxorubicin Doxil (Caelyx) Alza-corporation AIDS-related Kaposi s sarcoma... 

Doxorubicin 1974 Osteogenic sarcoma, Hodgkin s disease, CML, soft tissue sarcoma Inhibitor of DNA replication, transcription, repair [20]... 

Doxorubicin (Adriamycin, Rubex) [Antineoplastic/ Anthrocycline Antibiotic] Uses Acute leukemias Hodgkin Dz NHLs soft tissue, osteo Ewing sarcoma Wilms tumor neuroblastoma bladder, breast, ovarian, gastric, thyroid, lung CA Action Intercalates DNA X DNA topoisomerases I II Dose 60-75 mg/m q3wk X w/ hqjatic impair IV use only X... 

Northfelt DW, Martin FJ, Working P, Volberding PA, Russell J, Newman M, Amantea MA, Kaplan LD. Doxorubicin encapsulated in liposomes containing surface-bound polyethylene glycol pharmacokinetics, tumor localization, and safety in patients with AIDS-related Kaposi s sarcoma. J Clin Pharmacol 1996 36 55-63. 

Sarcomas are tumors of mesenchymal origin, arising in skeletal tissues and extra-skeletal connective tissues including the nerves. They are very rare and mainly effect a younger population. Sarcomas of soft tissues are relatively insensitive to drug treatment and are therefore not discussed in detail in this chapter. A systematic review of fourteen trials of doxorubicin-based adjuvant chemotherapy for the treatment of soft tissue sarcomas involving 1568 patients concluded Doxorubicin-based adjuvant chemotherapy appears to significantly improve time to local and distant recurrence and overall recurrence-free survival in adults with localised resectable soft tissue sarcoma. There is some evidence of a trend towards improved overall survival (see Sarcoma Meta-analysis Collaboration, 1999). 

Dacarbazine is the most active agent used in metastatic melanoma, producing a 20% remission rate. It is also combined with doxorubicin and other agents in the treatment of various sarcomas and Hodgkin s disease. 

Doxorubicin is one of the most effective agents used in the treatment of carcinomas of the breast, ovary, endometrium, bladder, and thyroid and in oat cell cancer of the lung. It is included in several combination regimens for diffuse lymphomas and Hodgkin s disease. Doxorubicin can be used as an alternative to daunorubicin in acute leukemias and is useful in Ewing s sarcoma, osteogenic sarcoma, soft-tissue sarcomas, and neuroblastoma. Some activity has been reported in non-oat cell lung cancer, multiple myeloma, and adenocarcinomas of the stomach, prostate, and testis. 

B16 melanoma, Walker sarcoma, and M5076 forming liver metastasis have been used in the preclinical evaluation of HPMA copolymer-adriamydn conjugates [36]. Other tumors useful for secondary screening are MS-2 sarcoma, NMU-1 murine lung adenocarcinoma, and murine adenocarcinoma Colon 26. These have been used by Zunino et al. [147] to determine the activity of poly (carboxylic acid) immobilized anthracyclines. Mice inoculated intramuscularly with Lewis lung carcinoma have been used by Pratesi et al. [215] to assess the effect of a poly-L-aspartic acid/doxorubicin conjugate. 

Doxorubicin Oxygen free radicals bind to DNA causing single- and double-strand DNA breaks inhibits topoisomerase II intercalates into DNA Breast cancer, Hodgkin s and non-Hodgkin s lymphoma, soft tissue sarcoma, ovarian cancer, non-small cell and small cell lung cancer, thyroid cancer, Wilms tumor, neuroblastoma Nausea, red urine (not hematuria) Cardiotoxicity (see text), alopecia, myelosuppression, stomatitis... 

Fig. 6. The combined effects doxorubicin and chitosan on tumor volume in sarcoma )80-bearmg mice.

Fig. 7, The combmed effects of doxorubicin and chitosan on body weighs in sarcoma 180-bearing mice.

Fig. 8. The preventive effects of chitosan on doxorubicin-induced gastrointestinal toxicity in sarcoma 180-beanng mice, a) small intestine weight b) sucrase activity in small intestinal mucosa.

Ewing s sarcoma is the second most common malignant bone tumor in children. The majority of patients have microscopic metastases at diagnosis the lung is the most common metastatic site. This sarcoma is a relatively rare disease with limited therapeutic options. The majority of patients are initially responsive to chemotherapy with vincristine, doxorubicin (Adriamycin), and cyclophosphamide. However, relapsed disease is usually extremely difficult to treat because of its resistance to chemotherapy (Zhou et al., 2001). 

Doxorubicin Adriamycin RDF, Rubex, others Acute leukemias carcinoma of bladder, breast, ovary, thyroid, and other tissues Hodgkin disease non-Hodgkin lymphomas several sarcomas Similar to daunorubicin... 

Northfelt, D. W., Dezube, B. J., Thommes, J. A., et al. Efficacy of PEGylated-liposo-mal doxorubicin in the treatment of AIDS-related Kaposi s sarcoma after failure of standard chemotherapy. J. Clin. Oncol. 15(2) 653-659. 1997. 

Daunorubicin (Daunomycin and Cerubidine) and doxorubicin (Adriamycin) bind to and cause the intercalation of the DNA molecule, thereby inhibiting DNA template function. They also provoke DNA chain scission and chromosomal damage. Daunorubicin is useful in treating patients with acute lymphocytic or acute granulocytic leukemia. Adriamycin is useful in cases of solid tumors such as sarcoma, metastatic breast cancer, and thyroid cancer. These agents cause stomatitis, alopecia, myelosuppression, and cardiac abnormalities ranging from arrhythmias to cardiomyopathy. 

Osteogenic sarcoma Doxorubicin, or methotrexate with leucovorin rescue initiated after surgery Cyclophosphamide, dacarbazine, interferon, ifosfamide plus mesna1... 

Miscellaneous sarcomas Doxorubicin plus dacarbazine Methotrexate, dactinomycin, ifosfamide plus mesna,1 vincristine, vinblastine... 

Various types of adherent cells were grown on a coverslip, which was then laid on top of the LAPS chip. Measurements were made for acidification of (1) normal human epidermal keratinocytes stimulated by epidermal growth factor (EGP) or organic chemicals, and of (2) human uterine sarcoma cells as a response to doxorubicin and vincristine (chemotherapeutic drugs). In addition, the inhibition (by ribavirin) of the viral infection of murine fibroblastic L cells by vesicular stomatitis virus (VSV) was investigated by following the acidification rate. A limitation of these studies is the requirement for a low-buffered medium (low bicarbonate content) to achieve maximum sensitivity [847]. 

Therapeutic applications Applications for these two agents differ despite their structural similarity and their apparently similar mechanisms of action. Doxorubicin is one of the most important and widely used anticancer drugs. It is used for treatment of sarcomas and a variety of carcinomas, including breast and lung, as well as acute lymphocytic leukemia and lymphomas. Daunorubicin is used in the treatment of acute lymphocytic and myelocytic leukemias. 

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