Phase I Study of Capecitabine and Oxaliplatin in Combination With the Proteasome Inhibitor Bortezomib in Patients With Advanced Solid Tumors

Cohen, Steven J.; Engstrom, Paul F.; Lewis, Nancy; Langer, Corey J.; McLaughlin, Susan; Beard, Mary; Weiner, Louis M.

doi:10.1097/coc.0b013e31805c142f

Cited by 12 publications

(6 citation statements)

References 23 publications

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“…It has been hypothesized that pre-existing subclinical, myeloma-related peripheral nerve damage may exist as a concurrent event responsible for the high incidence of CIPN in this specific population of cancer patients. This possibility is supported by the observation that the incidence of clinically relevant CIPN is lower in clinical trials with bortezomib in the treatment of solid tumors than in the treatment of hematologic malignancies [11].…”

Section: Epidemiologymentioning

confidence: 97%

Chemotherapy-Induced Neuropathy

Cavaletti

Alberti

Frigeni

et al. 2010

Curr Treat Options Neurol

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Chemotherapy-induced peripheral neurotoxicity (CIPN) is one of the most severe and unpredictable side effects of modern anticancer treatment. In recent years, a clear understanding of the importance of an integrated approach to CIPN has become evident, and efforts are increasing to better characterize its features and to identify more accurate methods to report and grade its occurrence. The clinically relevant impact of CIPN on cancer patients has been known for a long time, but knowledge of its pathogenetic aspects is still very limited. This incomplete knowledge is one of the major limitations in identifying targets for evidence-based neuroprotective strategies. Nevertheless, several studies have been devoted to the prevention or at least the effective treatment of symptoms secondary to peripheral nerve damage and to the early identification of patients at high risk of developing severe CIPN. Unfortunately, none of these studies has been successful and the optimal management of CIPN patients is still an unmet clinical need. Therefore, the modification of chemotherapy is currently the only available approach to limit the severity of neuropathy in the vast majority of patients. The indications for treatment modification are not universally accepted and they can differ among the various drugs. Generally, treatment modification should be considered as soon as symptoms and signs impair the daily life activities of the patient, but the possibility of a delayed worsening of CIPN after treatment withdrawal ("coasting") should always be considered, and delay of modification decisions should be avoided.

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Section: Epidemiologymentioning

confidence: 97%

Chemotherapy-Induced Neuropathy

Cavaletti

Alberti

Frigeni

et al. 2010

Curr Treat Options Neurol

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“…Few studies in that regard have been performed, but uncontrolled trials suggest no increase in the incidence of severe peripheral neuropathy when oxaliplatin is associated with vinca alkaloids 32 , taxanes 33 , and proteasome inhibitors 34 .…”

Section: The Peripheral Nervesmentioning

confidence: 99%

Oxaliplatin: A Review in the Era of Molecularly Targeted Therapy

2011

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molecularly targeted anticancer therapy with conventional cytotoxic chemotherapy. Such combinations can come about only through rational design of clinical trials, taking into account the pharmacology and clinical development of the drugs involved. It is therefore worthwhile revisiting classical chemotherapy agents, because this renewed knowledge could provide a foundation for future trials.Oxaliplatin is the newest platinum derivative in standard chemotherapy. Here, we review oxaliplatin from the pharmacologic and drug development perspectives, and we comment on possible associations of this drug with molecularly targeted therapy. CHEMICAL AND PHYSICAL PROPERTIES AND BIOTRANSFORMATIONOxaliplatin differs from cisplatin in that the amine groups of cisplatin are replaced by diaminocyclohexane (dach). The molecular weight of oxaliplatin is 397.3. It is slightly soluble in water, less so in methanol, and almost insoluble in ethanol and acetone 1 . Its full chemical name, oxalato(transl-1,2-diaminocyclohexane)platinum, refers to the presence of an oxalate "leaving group" and the dach carrier ligand, which are responsible, at least in part, for its unique properties 2,3 . For example, unlike cisplatin, oxaliplatin in plasma rapidly undergoes non-enzymatic transformation into reactive compounds because of displacement of the oxalate group, a process that complicates its pharmacokinetic profile. Most of the compounds appear to be pharmacologically inactive, but dichloro(dach) platinum complexes enter the cell, where they have cytotoxic properties. MECHANISMS OF ACTIONVarious mechanisms of action are ascribed to oxaliplatin. Like other platinum-based compounds, oxaliplatin exerts its cytotoxic effect mostly through dna damage. Apoptosis of cancer cells can be caused by formation of dna lesions, arrest of dna synthesis, ABSTRACT ObjectiveTo review preclinical and clinical data for oxaliplatin in the current context of molecularly targeted therapy.

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“…First, many authors have shown a better antitumor activity, in terms of a higher reduction in tumor growth without significantly increasing toxicity, exerted by bortezomib when used in combination with other chemotherapeutic agents in different preclinical studies. Based on these findings, to date various clinical trials are ongoing in different hematologic and solid tumors (3,(18)(19)(20). Second, fenretinide, unlike other retinoids, is well tolerated in humans, but it is only partially efficacious due to both a scanty oral delivery and a rapid metabolism (21).…”

mentioning

confidence: 99%

The Combined Therapeutic Effects of Bortezomib and Fenretinide on Neuroblastoma Cells Involve Endoplasmic Reticulum Stress Response

Pagnan¹,

Paolo²,

Carosio³

et al. 2009

Clinical Cancer Research

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Purpose: The proteasome inhibitor bortezomib inhibited cell growth and angiogenesis in neuroblastoma. Bortezomib has been shown to induce synergistic activity when combined with other antineoplastic agents. Here we have investigated the antitumor activity of bortezomib in combination with fenretinide, a synthetic retinoid, against neuroblastoma cells. Experimental Design: Different neuroblastoma cell lines were tested for sensitivity to bortezomib and fenretinide, given alone or in different dose-dependent and time-dependent combination schedules. Cell proliferation, cell viability, and apoptosis were evaluated by measuring 3 H-thymidine incorporation, trypan blue staining, DNA fragmentation, and western blot analysis. Angiogenesis was assessed by the chick embryo chorioallantoic membrane assay. An orthotopic neuroblastoma mouse model was used to examine in vivo sensitivity. Results: Each compound alone was able to induce a dose-dependent inhibition of cell proliferation, with a significant enhanced antiproliferative effect for the drugs used in combination. This inhibition was characterized by marked G 2 -M and G 1 cell cycle arrest with nearly complete depletion of S phase. Bortezomib and fenretinide in association triggered an increased apoptosis through activation of specific genes of the endoplasmic reticulum stress compared with either drug tested alone. Tumor-bearing mice treated with bortezomib plus fenretinide lived statistically significantly longer than mice treated with each drug alone. Histologic evaluation and chorioallantoic membrane analysis of primary tumors showed that the combined therapeutic activity of bortezomib and fenretinide rested upon antitumor and antiangiogenic mechanisms. Conclusions: These findings provide the rationale for the development of a new therapeutic strategy for neuroblastoma based on this pharmacologic combination.

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Phase I Study of Capecitabine and Oxaliplatin in Combination With the Proteasome Inhibitor Bortezomib in Patients With Advanced Solid Tumors

Cited by 12 publications

References 23 publications

Chemotherapy-Induced Neuropathy

Chemotherapy-Induced Neuropathy

Oxaliplatin: A Review in the Era of Molecularly Targeted Therapy

The Combined Therapeutic Effects of Bortezomib and Fenretinide on Neuroblastoma Cells Involve Endoplasmic Reticulum Stress Response

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