Treatment of solid tumors

One commonly used agent is the antimetabolite 5-fluorouracil (5-FU), which is frequently used as an adjuvant therapy in conjunction with surgical excision in the treatment of solid tumors. p53 can directly trigger apoptosis in cells exposed to 5-FU in vitro [1]. In addition, there is a substantial amount of clinical... 

Sava, G. Alessio, E. Bergamo, A. Mestroni, G. Sulfoxide Ruthenium Complexes Non Toxic Tools for the Selective Treatment of Solid Tumor Metastases In Metallopharmaceuticals l DNA Interactions, Clarke, M. J. and Sadler, P. J., Ed. Springer-Verlag Berlin, 1999 Vol.l, pp 143-170. 

Needham D, Dewhirst MW. The development and testing of new temperature-sensitive drug delivery system for treatment of solid tumors. Adv Drug Deliv Rev 2001 53 285-305. 

Denduluri N, Swain SM. (2008) Ixabepilone for the treatment of solid tumors A review of clinical data. Expert Opin Investig Drugs 17 423 35. 

Of all the 4-anilino-3-quinoHnecarbonitrile dual Src/Abl inhibitors, the most extensively profiled analog is SKI-606. Pharmacokinetics showed SKI-606 to have an oral bio availability in nude mice of 18% and a half-hfe of 8.6 hours with a large volume of distribution [122]. SKI-606 was active in several colon tumor xenograft models when dosed orally at 25-150 mg/kg daily for 21 days with no weight loss or overt toxicity noted in the animals. On the basis of its pre-clinical properties, SKI-606 entered clinical trials in 2004 for the treatment of solid tumors and will soon be entering trials for the treatment of CML. 

In addition to in vivo studies in models of CML, BMS-354825 has also been studied in models of solid tumors. BMS-354825 was efficacious in head and neck squamous cell carcinoma and non-small cell lung cancer animal models [151]. Based on this activity, BMS-354825 has been advanced into clinical trials for the treatment of solid tumors. 

State-of-the-art and forward-looking, Chemoradiation in Cancer Therapy offers oncologists a thorough understanding of today s best current and future strategies available for the treatment of solid tumors by chemoradiation therapy. 

Dannomycin was the first antibiotic to be used in the treatment of leukemia in human(39-40). Dannomycin (Fig. 11) and the closely related adriamycin (14-hydro dannomycin) are both widely used in the treatment of human tumors. Even though these substances are closely related to each other, they have q.uite distinct biological activities. Daunomycin is used in the treatment of leukemias, whereas adriamycin is used in the treatment of solid tumors. These agents are believed to act by inhibiting both IMA replication and transcription. 

Murry, J. (2000). Monoclonal antibody treatment of solid tumors a coming of age. Semin. Oncol. 27(6), 64-70. Senter, P. Springer, C. (2001). Selective activation of anticancer prodrugs by monoclonal antibody-enzyme conjugates. Adv. Drug Deliv. Rev. 53(3), 247-264. 

Schering Plough demonstrated the kinetic resolution of a secondary amine (24) via enzyme-catalyzed acylation of a pendant piperidine (Scheme 7.13) [32]. The compound 27 is a selective, non-peptide, non-sulfhydryl farnesyl protein transfer inhibitor undergoing clinical trials as a antitumor agent for the treatment of solid tumors. The racemic substrate (24) does not contain a chiral center but exists as a pair of enantiomers due to atropisomerism about the exocylic double bond. The lipase Toyobo LIP-300 (lipoprotein lipase from Ps. aeruginosa) catalyzed the isobu-tylation of the (+) enantiomer (26), with MTBE as solvent and 2,2,2-trifluoroethyl isobutyrate as acyl donor [32]. The acylation of racemic 24 yielded (+) 26 at 97% and (-) 25 at 96.3% after 24h with an E >200. The undesired enantiomer (25)... 

Scheme 7.13 Enzymatic resolution for the synthesis of 27 for the sythesis of selective, non-peptide, non-sulfhydryl farnesyl protein transfer inhibitor currently undergoing phase II clinical trials for the treatment of solid tumors.

Cisplatin, an anticancer agent used for the treatment of solid tumors, is prepared by the reaction of ammonia with potassium tetrachloroplatinate ... 

Grande C, Firvida JL, Navas V, Casal J. 2006. Interleukin-2 for the treatment of solid tumors other than melanoma and renal cell carcinoma. Anticancer Drugs. 17 1-12. 

Forssen, E. A. and Ross, M. E. (1994) Daunoxome registered treatment of solid tumors preclinical and clinical investigations. Liposome Res., 4 481-512. 

Recently, there has been renewed interest in developing vaccines for use in cancer treatment. The main factors giving impetus to this therapeutic approach include a better understanding of the immune system, the identification of several T cell-specific tumor antigens, more effective adjuvants, and the ability to construct more immunogenic molecules using recombinant DNA techniques (Murray et al., 2000). Current vaccine strategies for the treatment of solid tumors tend to focus on the cellular arm of the immune response. 

Murray, J. L. 2000. Monoclonal antibody treatment of solid tumors. Sem. Oncol. 27 64—70. 

Giamas G et al (2010) Kinases as targets in the treatment of solid tumors. Cell Signal 22 984-1002... 

Further studies have validated this hypothesis, in part,4 and ultimately this inventive premise was borne out in clinical practice. As a result, 5-FU (5) was eventually approved for treatment of solid tumors, such as breast, colorectal, and gastric cancers. Marketed as Adrucil when administered intravenously, 5-FU can be used either as monotherapy or combination therapy with various cytotoxic drugs and biochemical modulators, such as leucovorin and methotrexate.5 Because 5-fluorouracil is not orally bioavailable, it must be administered by continuous infusion to optimize its efficacy due to its short half-life in plasma. In addition, 5-FU has poor selectivity toward tumors in vivo, and its distribution into tissues such as bone marrow, the gastrointestinal tract, the liver and skin causes high incidences of toxicity. In addition, in spite of its limited lipid solubility, 5-fluorouracil diffuses readily across the blood-brain barrier into cerebrospinal fluid and brain tissue.1,5... 

The most advanced products based on the implantable gel technology include the Intradose (cisplatin/ epinephrine) injectable gel for treatment of solid tumors and the Advasite (fluorouracil/epinephrine)... 

In spite of these promising results, the tumor uptake of 9°Y-SU015 is still relatively low (around 1.5% ID/g at 24 h post injection). The biodistribution data in the c-neu Oncomouse model also show that a small part of 9°Y-SU015 is excreted via the hepatobiliary route. The radioactivity levels in blood, kidney, and liver are relatively high, which makes 9°Y-SU015 less than ideal as a new therapeutic radiopharmaceutical for the treatment of solid tumors. 

Therapeutic applications Cisplatin has found wide application in the treatment of solid tumors such as metastatic testicular carcinoma in combination with vinblastine (see p. 390) and bleomycin (see p. 386), ovarian carcinoma in combination with cyclophosphamide (see p. 388), or alone for bladder carcinoma. Carboplatin is employed when patients cannot be vigorously hydrated as is required for cisplatin treatment, or if they suffer from kidney dysfunction or are prone to neuro- or ototoxicity. 

The development of the platinum (Pt) -containing cytotoxic drugs for the treatment of solid tumors is a major success story of analogue-based drug discovery. Very soon after the introduction of the first Pt complex into clinical practice, three main goals for the development of subsequent derivatives were formulated ... 

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