Sarcoma treatment

M. Korbelik, I. Cecic (1999). Contribution of myeloid and lymphoid host cells to the curative outcome of mouse sarcoma treatment by photodynamic therapy. Cancer Lett., 137, 91-98. 

Not only is TCDO a potent therapeutic agent in acute radiation syndrome, but treatment using TCDO from days 4—11 after TBI increases the survival rate in rats for up to one year, protects against the development of late GI ulcers, and also reduces the development of y-ray-induced leukemias and malignant epitheHal tumors, but not sarcomas (202). The anticarcinogenic effect of TCDO maybe related to the inhibition of PGs, which promote carcinogenesis, or to immunostimulation, which may result in a more effective elimination of malignant cells. 

Dacarbazine is the most active compound used for treating metastatic melanoma. It is also combined with anthracyclines and other cytostatics in the treatment of different sarcomas and Hodgkin s disease. Dacarbazine may cause severe nausea and vomiting. Myelosuppres-sion results in leukopenia and thrombocytopenia. Alopecia and transient abnormalities in renal and hepatic function also occur. 

MTX is part of curative therapeutic schedules for acute lymphoblastic leukemias (ALL), Burkitt s lymphoma, and choriocarcinoma. It was also used in adjuvant therapy of breast cancer. High dose MTX with leucovorin rescue can induce about 30% remissions in patients with metastatic osteogenic sarcoma. MTX is one of the few antineoplastic drugs that can be safely administered intrathecally for the treatment of meningeal metastases and leukemic infiltrations (routine prophylaxis in ALL). In addition, MTX can be used as an immunosuppressive agent for the treatment of severe rheumatoid arthritis and psoriasis. 

Cytokines and biological response modifiers represent a broad class of therapeutic agents that modify the hosts response to cancer or cancer therapies. The enormous body information about their clinical uses and their side effects is beyond the scope of this essay that can only give illustrative examples. For an up-to-date information the reader can resort to reference [5]. As many as 33 different interleukins are known and the list continues to grow IL-2 used in the treatment of kidney cancer is one example. Interferon alpha is used for chronic myelogenous leukeia, hairy cell leukaemia and Kaposi s sarcoma. Interferons are also used in the treatment of chronic infections such as viral hepatitis. Tumor necrosis factor (alpha), G/GM/M-CSF, and several other cellular factors are used in treatment of various cancers. Many of these cytokines produce serious side effects that limit their use. 

Kaposi sarcoma (KS) - an angiogenic-inflammatory neoplasm - is the most prevalent cancer in HIV-infected patients and its appearance is preceded by infection with human Heipesvitus-8 (HHV-8). Although chemotherapy has become the treatment of choice approved by the FDA, there are also good response rates in patients treated with IFN-a. Fortunately, today highly active antiretroviral therapy (HAART) has dramatically decreased the incidence of KS in AIDS patients. 

Haverkos HW, Pinsky PF, Drotman DP, etal Disease manifestation among homosexual men with acquired immunodeficiency syndrome a possible role of nitrites in Kaposi s sarcoma. Sex Transm Dis 12 203-208, 1985 Haverkos HW, Kopstein AN, Wilson H, et al Nitrite inhalants history, epidemiology, and possible links to AIDS. Environ Health Perspect 102 858-861, 1994 Hernandez-Avila CA, Ortega-Soto HA, Jasso A, et al Treatment of inhalant-induced psychotic disorder with carbamazepine versus haloperidol. Psychiatr Serv49 812— 815, 1998... 

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. 

While the exact mechanism of action remains unclear, dacarbazine appears to inhibit DNA, RNA, and protein synthesis. Dacarbazine disappears rapidly from the plasma, with a terminal half-life of about 40 minutes. Dacarbazine has shown clinical benefit in the treatment of melanoma, Hodgkin s lymphoma, and soft tissue sarcomas. Side effects include myelosuppression, severe nausea and vomiting, and a flulike syndrome that starts about 7 days after treatment and lasts 1 to 3 weeks. 

Severe, and in particular chronic, infection can also sometimes induce anaemia, which is often made worse by drugs used to combat the infection. For example, anaemia is evident in 8 per cent of patients with asymptomatic HIV infection. This incidence increases to 20 per cent for those with AIDS-related complex, and is greater than 60 per cent for patients who have developed Kaposi s sarcoma. Up to a third of AIDS patients treated with zidovudine also develop anaemia. Again, several trials have confirmed that EPO treatment of AIDS sufferers (be they receiving zidovudine or not) can increase haematocrit values and decrease transfusion requirements. 

The DNA minor groove binder brostallicin (PNU-166196, 24), currently in Phase 2 clinical trials for the treatment of soft-tissue sarcoma, exhibited potent... 

Humphrey and Seal9 (U.S.A.) reported in 1959 detailed experiments on the ECT of sarcoma-180 tumors in nearly 500 mice. In a typical experiment, 18 test animals and 18 control animals were used the ECT was done with 3 ma current, at 6 V for 3 hours a day, for 24 days. They observed that after such a lengthy treatment, the mean volume of test tumors was about 15% of the mean tumor volume of the control group seven mice showed complete tumor regression as a result of ECT. Total regression means that the tumor has decreased progressively in volume, hardened, dropped off, leaving a new skin surface at the former tumor site. 

Because of its antiviral and anticancer effects, IFN-a is used in the treatment of hepatitis and various forms of cancer, such as Kaposi s sarcoma, non-Hodgkin s lymphoma, and hairy cell leukemia. Exhibit 4.8 describes the treatment of hepatitis C with IFN- . IFN-jS is used for treating multiple sclerosis, a chronic disease of the nervous system. The medical application of IFN-y is for cancer, AIDS, and leprosy. 

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. 

Trabectedin is licensed for the treatment of advanced soft-tissue sarcoma when treatment with anthracyclines and ifosfamide has failed or is contraindicated. It is administered by intravenous infusion. Trabectedin may cause hepatobiliary disorders and for this reason hepatic function should be evaluated before starting treatment and during treatment. Dexamethasone is administered intravenously with trabectedin for its anti-emetic and hepatoprotective effects. As with other antineoplastic drugs, trabectedin causes nausea and vomiting and bone-marrow suppression as side-effects. 

Trabectedin (36 Yondelis, ecteinascidin-743, ET-743 Zelfia and Johnson and Johnson, 2007), a tetrahydroisoquinoline alkaloid produced hy the ascidian Ecteinascidia turbinate,received approval for its sale in Europe, Russia and South Korea by Zelfia and Johnson and Johnson under the brand name YondelisT for the treatment of advanced soft tissue sarcoma (STS). Trabectedin (36) binds to the minor groove of DNA and inhibits cell proliferation by disrupting the cell cycle. 

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... 

Leahy M, Ray-Coquard 1, Verweij J, Le Cesne A, Duffaud F, Hogendoom PC, Fowst C, de Balincourt C, di Paola ED, van Glabbeke M, Judson 1, Blay JY. (2007) European Organisation for research and treatment of cancer soft tissue and bone sarcoma group. Ear J Cancer 43 308-315. 

Bristol-Myers Squibb Co. manufactures and distributes paclitaxel (brand name, Taxol, and generically known as taxol), which the FDA has approved for treatment of ovarian, breast and lung cancers and AIDs-related Kaposi s sarcoma. Bristol s patent listings in the Orange Book and the related patent infringement suits demonstrate that invalid patents in combination with the lengthy pendency of a patent application can potentially generate an additional 30-month stay. 

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