Bortezomib, chemically a dipeptidyl boronic acid from the amino acids leucine and phenyl alanine, is a proteosome inhibitor. It causes accumulation of the growth inhibitory molecules p21 and p27 subsequently leading to cell arrest and cell death. • Irinotecan is a prodrug, whose active metabolite inhibits Topoisomerise 1 leading to generation and accumulation of irreversible double-strand breaks in DNA during synthesis and finally cell death. Preclinical studies reported anti-tumour response of bortezomib and Irinotecan combination and suggested that prevention of NF-kB activation by bortezomib may enhance Irinotecan mediated cytotoxicity.
The present study evaluated the safety and biologic effects of co-administration of bortezomib and irinotecan in patients with advanced solid tumors. The rationale for combining bortezomib with irinotecan is based on observations of antitumor activity in a murine model of colon tumor xenografts. Growth was inhibited to a greater extent by bortezomib plus SN-38, the active metabolite of irinotecan, than the sum of the activities of either agent alone. This suggested, given the different mechanisms of action, that the two agents might be synergistic in a clinical setting.
17 Moreover, bortezomib inhibited SN-38-induced activation of the transcription factor nuclear factor _B (NF_B). 17 This activation has been shown to be associated with irinotecan resistance because it suppresses apoptosis. Irinotecan-induced protection from apoptosis in CRC cell lines was reversed by inhibition of NF_B, enhancing the antitumor response, and further supporting the use of combination bortezomib plus irinotecan in clinical trials in patients with advanced CRC.
18 A similarly impressive antitumor effect of the bortezomib and irinotecan combination was observed in mice bearing BXPC3 pancreatic tumor xenografts. 18 Those findings suggested that bortezomib may enhance irinotecan-mediated cytotoxicity by preventing NF-kB activation. In a phase I trial in patients with advanced solid tumors, including 23 patients with CRC, bortezomib plus irinotecan was welltolerated without additive toxicities. 19 Nausea, vomiting, and diarrhea were the principle dose-limiting toxicities, leading to maximum tolerated doses (MTD) of 1.
3 mg/m2 bortezomib and 125 mg/m2 irinotecan. The results of a Phase I clinical trial to evaluate the safety and biologic effects of bortezomib and irinotecan coadministered to patients with advanced solid tumors are described in this report. This study was designed to establish the maximum tolerated dose (MTD) of bortezomib on Days 1, 4, 8, and 11 together with irinotecan on Days 1 and 8 of each 21- day cycle. Pharmacodynamic studies also were undertaken to evaluate the effect of concurrently administered irinotecan on proteasome inhibition in peripheral blood cells. METHODS. Patients who had received _1 prior chemotherapy regimen were eligible.
Patients received bortezomib (1. 0 mg/m2, 1. 3 mg/m2, or 1. 5 mg/m2) on Days 1, 4, 8, and 11 and received irinotecan (from 50 mg/m2 to 125 mg/m2) on Days 1 and 8 of each 21-day cycle for a maximum of 8 cycles. Bortezomib followed irinotecan on coadministration days in Cycle 1 and Cycles 3 through 8 but preceded irinotecan in Cycle 2 to assess the effect of administration sequence on bortezomib pharmacodynamics. RESULTS. Fifty-one enrolled patients with malignancies, including colorectal cancer (n ? 23 patients), lung cancer (n ? 6 patients), gastroesophageal cancer (n ?6 patients), and pancreatic cancer (n ? 3 patients), received _1 dose of study drug.
Nausea, vomiting, and diarrhea were the principal dose-limiting toxicities and led to the maximum tolerated doses of 1. 3 mg/m2 bortezomib and 125 mg/m2 irinotecan. The most common grade _3 bortezomib-related nonhematologic adverse events were fatigue (n ? 5 episodes), diarrhea (n ? 4 episodes), and nausea (n ? 4 episodes). grade _3 bortezomib-related hematologic adverse events included neutropenia (n ? 6 episodes) and thrombocytopenia (n ? 4 episodes) and rarely were dose limiting.
Of 34 evaluable patients, no objective responses according to the Response Evaluation Criteria in Solid Tumors were seen; 10 patients achieved stable disease. The degree of proteasome inhibition in whole blood indicated that the biologic activity of bortezomib was unaffected by irinotecan coadministration The coadministration of 1. 3mg/m2 Bortezomib with 125 mg/m2 Irinotecan was tolerated and the adverse events were manageable. There was no additive side effects noted. The drug administration sequence did not have an effect on the pharmacodynamic activity of Bortezomib.
These findings call for an effort study the drug combination for its effectiveness on treating the tumors sensitive to Irinotecan. Bortezomib The peptide boronate bortezomib (N-acyl-pseudo dipeptidyl boronic acid), also known as PS-341 or Velcade™ (Millennium Pharmaceuticals), is a dipeptide that contains a boronic acid instead of a carboxylic acid at the C-terminus. Bortezomib’s boronic acid reversibly binds to the chymotrypsin-like ? 5 subunit of the catalytic chamber of the 20S particle and inhibits proteasome function [8].
Bortezomib’s interaction with the proteasome is shown in Figure 2. Bortezomib was an expedited product of exemplary collaboration between academia and industry. It is the first therapeutic proteasome inhibitor to be tested in humans [9]. Initial laboratory findings showed that blocking the proteasome in vivo did not immediately alter the normal life cycle of the cell [10]. The ensuing studies revealed that the proteasome was important in the activation of NF-? B [11] implicated as one of the mechanisms of tumor cell resistance to apoptosis.
Based on these observations, in August 1994, Julian Adams examined bortezomib as a possible anti-cancer molecular targeting agent. By 1997, it was also shown that bortezomib could have potential influence on inhibiting tumor growth and metastasis in a mouse model of lung cancer [12]. The phase I clinical trials at the University of North Carolina presented evidence that bortezomib was effective in treating multiple myeloma. It was an exciting observation that bortezomib erased all signs of cancer from a 47-year old woman, who was diagnosed with advanced stages of multiple myeloma.
Following phase II clinical trials, bortezomib was approved on May 13, 2003 by the US FDA under a Fast-Track Application, as an injectable small molecule for the treatment of multiple myeloma. In December 2006, it was approved for the treatment of relapsed or refractory mantle cell lymphoma. It remains thus far the only proteasome inhibitor approved for clinical use. Proteasome inhibition is a promising new investigational avenue for cancer therapy. The proteasome inhibitor bortezomib (previously known as PS-341) is a novel, small molecule that has shown antitumor activity in preclinical studies and has entered clinical trials, with encouraging results to date.
Preclinically, bortezomib has exhibited potent activity, enhanced the sensitivity of cancer cells to traditional tumoricidal agents, and appeared to overcome drug resistance. Targeting the ubiquitin-proteasome pathway has emerged as a rational approach in the treatment of human cancer. The approval of bortezomib by the US Food and Drug Administration (FDA) represented a significant milestone as the first proteasome inhibitor to be implemented in the treatment of malignant disease.
Bortezomib has shown a positive clinical benefit either alone or as a part of combination therapy to induce chemo-/radiosensitization or overcome drug resistance. Another important mechanism of bortezomib is through suppression of the NF-? B signaling pathway resulting in the down-regulation of its antiapoptotic target genes. Although the majority of success achieved with bortezomib has been in hematological malignancies, its effect toward solid tumors has been less than encouraging. Some phase I clinical studies on solid tumors also showed promising data when bortezomib was used either as a single agent or as a part of combination therapy.
Bortezomib alone showed anti-tumor activity in patients with advanced androgen-independent prostate cancer [14], and the combination of bortezomib and carboplatin elicited an overall response rate of 47% in recurrent ovarian or primary peritoneal cancer [58]. Based on phase I studies demonstrating that bortezomib has manageable toxicities in patients with advanced cancers, phase II trials have been initiated for both solid and hematological malignancies. The proteasome is a multicatalytic protein complex whose principal task is the degradation of a large array of proteins within the cell.
Its substrates include proteins involved in cell cycle regulation, tumor suppression, apoptosis, transcription, and angiogenesis, among others. This makes the inhibition of the proteasome a promising novel therapeutic approach to cancer treatment. Bortezomib (Velcade) is the first proteasome inhibitor to have shown anti-cancer activity and reached clinical trials. Preclinical and early clinical trials in both solid tumors and hematological malignancies demonstrate that bortezomib is a relatively well-tolerated and active agent, either alone or in combination with traditional chemotherapeutic drugs.
Clinical trials that may help delineate the role of bortezomib in the treatment solid tumors either as single agent or in combination are ongoing.
Poster Bortezomib 3 https://www. researchgate. net/publication/8043134_Discovery_Development_and_clinical_applications_of_bortezomib Rationale The combination of bortezomib 1. 3 mg/m2 and irinotecan 125 mg/m2 was tolerated with and had a manageable toxicity profile. The use of bortezomib in combination with irinotecan did not appear to 2696 CANCER December 1, 2006 / Volume 107 / Number 11 result in additive gastrointestinal or hematologic toxicities.
Administration of irinotecan did not interfere with the pharmacodynamic activity (proteasome inhibition) of bortezomib. These results warrant further investigation of combination treatment with bortezomib and irinotecan, especially in cancers that are known to be responsive to irinotecan therapy. evaluate the efficacy and toxicity of bortezomib with or without irinotecan, in patients with relapsed or refractory colorectal cancer (CRC).