Antitumor efficacy

The interstrand cross-link also induces DNA bending.72 X-ray and NMR studies on this adduct show that platinum is located in the minor groove and the cytosines of the d(GC) base pair involved in interstrand cross-link formation are flipped out of the helix stack and a localized Z-form DNA is observed.83-85 This is a highly unusual structure and very distorting—implications for differential repair of the two adducts have been addressed. Alternatively, the interstrand cross-link of the antitumor inactive trans-DDP is formed between a guanine (G) and its complementary cytosine (C) on the same base p a i r.86,87/ nms- D D P is sterically incapable of producing 1,2-intrastrand adducts and this feature has been cited as a dominant structural reason for its lack of antitumor efficacy. It is clear that the structural distortions induced on the DNA are very different and likely to induce distinctly different biological consequences. 

Bernstein, A., Hurwitz, E., Maron, R., Arnon, R., Sela, M., and Wilchek, M. (1978) Higher antitumor efficacy of daunomycin when linked to dextran In vivo and in vitro studies. /. Natl. Cancer Inst. 60, 379-384. 

The main potential utility of the pure antiestrogens is in the treatment of breast cancer. Several studies on their effects on the breast demonstrate both the pure antiestrogenic action of the tested compounds and their beneficial effects on breast cancer treatment. In experiments conducted in nude mice xenotrans-planted with two different human estradiol-dependent breast tumors, a single injection of fulvestrant provided an antitumor efficacy equivalent to that of daily tamoxifen treatment for at least 4 weeks (Wakeling et al. 1991). Additionally, RU 58668 was able to induce up to 30% disappearance of MCF-7 breast... 

Kelland et al. (124, 125) have developed a series of trans-platinum(IV) complexes such as 17 (JM335) with marked antitumor efficacy against both murine and human s.c. tumor models (125). It is... 

Ciomei M, Croci V, Ciavolella A, Ballinari D, Pesenti E. Antitumor efficacy of edotecarin as a single agent and in combination with chemotherapy agents in a xenograft model. Clin. Cancer Res. 2006 May 1 12(9) 2856-61. 

Further investigations revealed that the superior antitumor efficacy of Leu-DOX was, indeed, due to site-selective activation and delivery of doxorubicin. At equitoxic intravenous doses of DOX and Leu-DOX (8 and 28 mg/kg, respectively, see above), the plasma levels of DOX attained were comparable, whereas differences were seen in tumor tissue concentrations [51]. The enzymes involved in the tumor-selective activation of Leu-DOX were not identified, although possible candidates include the cathepsin family of proteases [47],... 

Mayer LD, Bally MB, Cullis PR, Wilson SL, Emerman JT. Comparison of free and liposome encapsulated doxorubicin tumor drug uptake and antitumor efficacy in the SCI 15 murine mammary tumor. Cancer Lett 1990 53 183. 

Boulay A, Zumstein-Mecker S, Stephan C, Beuvink I, Zilbermann F, Haller R, Tobler S, Heusser C, O Reilly T, Stolz B, Marti A, Thomas G Lane HA. (2004) Antitumor efficacy of intermittent treatment schedules with the rapamycin derivative radOOl correlates with prolonged inactivation of ribo-somal protein s6 kinase 1 in peripheral blood mononuclear cells. Cancer Res 64 252-261. 

The functionality associated with N-1 of the vindoline portion of the bisindole alkaloids confers much biological diversity to these compounds. This property is exemplified by the differences in the cellular pharmacology, antitumor efficacy, and toxicity of vinblastine (1) and vincristine (2). Since 1 is isolated from extracts of Catharanthus in approximately 10-fold greater yield, it is not surprising that several oxidative methods have... 

A number of substituted bisindole oxazolidinedione derivatives were prepared using the methods described above (Table VI) (79-81). When examined for their ability to induce a mitotic block in CHO cells, these compounds were active from 2 to 0.002 p.g/ml (Table VII), and compounds having the greatest degree of potency in this in vitro system were evaluated in several experimental tumor systems (Table VIII). The in vitro potency of these compounds appears to correlate with their in vivo potency as reflected by the minimum effective dose that could be administered without toxicity. Several of these compounds were evaluated for their antitumor efficacy when administered by the oral route (Table IX). Compounds 96 and 107 were shown to be exceptionally active in this regard. 

Siemann DW, Jiang JB, Balias L, Janzen W (1993) Threo-dihydrosphingosine potentiates the in vivo antitumor efficacy of dsplatin and adriamycin. Proc Am Assoc Cancer Res 34 410,2452... 

Shalinsky DR, Brekken J, Zou H, Bloom LA, McDermott CD, ZookS, et al. Marked antiangiogenic and antitumor efficacy of AG3340 in chemoresistant human non-small cell lung cancer tumors single agent and combination chemotherapy studies. Clin Cancer Res 1999 5 1905-1917. 

Wedge SR, Ogilvie DJ, Dukes M, Kendrew J, Curwen JO, Hennequin LF, et al. ZD4190 an orally active inhibitor of vascular endothelial growth factor signaling with broad-spectrum antitumor efficacy. Cancer Res 2000 60 970-975. 

Administration of some anticancer drugs by continuous infusion has been shown to improve their therapeutic index through selective reduction of toxicity with retained or enhanced antitumor efficacy. 

Mitoxantrone is active against breast carcinomas, leukemias, and lymphomas. Its antitumor efficacy in patients with breast cancer is slightly lower than that of doxorubicin. Its major toxicity is myelosuppression mucositis and diarrhea also may occur. Mitoxantrone produces less nausea, alopecia, and cardiac toxicity than does doxorubicin. 

Shojamanesh H, Gibril F, Louie A, Ojeaburu JV, Bashir S, Abou-Saif A, Jensen RT. Prospective study of the antitumor efficacy of long-term octreotide treatment in patients with progressive metastatic gastrinoma. Cancer 2002 94(2) 331 13. 

Kimura, Y., et al. 2002. P-glycoprotein inhibition by the multidrug resistance-reversing agent MS-209 enhances bioavailability and antitumor efficacy of orally administered paclitaxel. Cancer Chemother Pharmacol 49 322. 

C. Heise, J. A. Sampson, A. Williams, F. McCormick, H. D. Von, and D. H. Kim, ONYX-015, an E1B gene-attenuated adenovirus, causes tumor-specific cytolysis and antitumoral efficacy that can be augmented by standard chemotherapeutic agents [see comments], Nat. Med. 3 639 (1997). 

C. C. Heise, A. M. Williams, S. Xue, M. Propst, and D. H. Kirn, Intravenous administration of ONYX-015, a selectively replicating adenovirus, induces antitumoral efficacy, Cancer Res. 59 2623 (1999). 

HER2-overexpressing breast cancer xenografts in vivo (243). Furthermore, trastuzumab enhanced the antitumor efficacy of multiple chemotherapeutic agents, including cisplatin, paclitaxel, and doxorubicin, in animal models (244-246). 

In parallel to these studies, carbamate compounds 1 and 11-14 were assessed for their antitumor efficacy in mouse cancer xenograft models.15 When implanted human colon cancer CXF280 xenografts were grown within mice for fourteen days, doses of test compounds were administered orally. After a three-week regimen, excised tumor volumes were measured and the percent inhibition of tumor growth was calculated. From this investigation, capecitabine (1) was found to be the most effective treatment, and was furthermore found not to cause intestinal toxicity.16 All of these preclinical observations contributed to the selection of capecitabine as a candidate for further development. 

Canti G, Nicolin A, Cubeddu R, Taroni P, Bandieramonte G, Valentini G. Antitumor efficacy of the combination of photodynamic therapy and chemotherapy in murine tumors. Cancer Lett 1998 125(l-2) 39-44. 

Batist, G., Ramakrishnan, G., and Rao, C. S. (2001), Reduced cardiotoxicity and preserved antitumor efficacy of liposome-encapsulated doxorubicin and cyclophosphamide compared with conventional doxorubicin and cyclophosphamide in a randomized, multicenter trial of metastatic breast cancer,/. Clin. Oncol., 19,1444-1454. 

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