Superiority of post-radiotherapy adjuvant chemotherapy with CCNU, procarrazine, and vincristine (PCV) over BCNU for anaplastic gliomas: NCOG 6G61 final report

Levin, Victor A.; Silver, Pamela; Hannigan, John F.; Wara, William M.; Gutin, Philip H.; Davis, Richard L.; Wilson, Charles B.

doi:10.1016/0360-3016(90)90096-3

Cited by 372 publications

(136 citation statements)

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“…7,9 Although toxicity and resistance are the major problems associated with alkylating agent chemotherapy, numerous alkylating agents remain the first line drugs to treat a variety of cancers. 6,10 Newly designed alkylating agents with increased efficacy and decreased adverse side effects are needed to improve the treatment of cancer.…”

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confidence: 99%

The novel DNA alkylating agent BO‐1090 suppresses the growth of human oral cavity cancer in xenografted and orthotopic mouse models

Sanjiv

Suman

et al. 2011

Intl Journal of Cancer

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Oral cancer is the fourth-most common cause of death in males and overall the sixth-most common cause of cancer death in Taiwan. Surgery, radiotherapy and chemotherapy combined with other therapies are the most common treatments for oral cavity cancer. Although cisplatin, 5-fluorouracil and docetaxel are commonly used clinically, there is no drug specific for oral cavity cancer. Here, we demonstrated that derivatives of 3a-aza-cyclopenta[a]indene, a class of newly synthesized alkylating agents, may be drugs more specific for oral cancer based on its potent in vitro cytotoxicity to oral cancer cells and on in vivo xenografts. Among them, BO-1090, bis(hydroxymethyl)-3a-aza-cyclopenta[a]indene derivative, targeted DNA for its cytotoxic effects as shown by inhibition of DNA synthesis (bromodeoxyuridine-based DNA synthesis assay), induction of DNA crosslinking (alkaline gel shift assay), and induction of DNA single-stranded breaks (Comet assay) and double-stranded breaks (c-H2AX focus formation). Following DNA damage, BO-1090 induced G1/S-phase arrest and apoptosis in oral cancer cell lines. The therapeutic potential of BO-1090 was tested in mice that received a xenograft of oral cavity cancer cell lines (SAS or Cal 27 cells). Intravenous injection of BO-1090 significantly suppressed tumor growth in comparison to control mice. BO-1090 also significantly reduced the tumor burden in orthotopic mouse models using SAS cells. There was no significant adverse effect of BO-1090 treatment with this dosage based on whole blood count, biochemical enzyme profiles in plasma and histopathology of various organs in mouse. Taken together, our current results demonstrate that B0-1090 may have potential as a treatment for oral cavity cancer.Oral cavity cancer involving the lesions occurred in the tongue, oropharynx and floor of the mouth is a prevalent type of cancer in developing countries such as India, Pakistan, Bangladesh and Taiwan. 1 In south-central Asia, it is the third-most common cancer, with an average incidence rate of 1 to 10 per 100,000 people. The incidence of oral cancer is also increasing in developed countries. 2 The treatments of oral cancer include surgery, radiation or chemotherapy, depending on the stage and nature of the tumor. 3,4 Unfortunately, only marginal improvement is seen in many patients, and a complete cure is often not achieved. Half of the patients diagnosed with oral cancer succumb to death within 5 years, and for those who survive, the quality of life remains poor. 1 Thus, development of a drug specific for oral cavity cancer is needed so that substantial improvement in treatment can be achieved.The cytotoxic and antitumor properties of alkylating agents are due to their ability to covalently bind to DNA. There are two types of DNA alkylating agents, monofunctional and bifunctional agents. Monofunctional alkylating agents mainly damage DNA by forming methylated adducts, whereas the damage induced by bifunctional alkylating agents includes monoadducts, intrastrand crosslinks and interstrand crossli...

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The novel DNA alkylating agent BO‐1090 suppresses the growth of human oral cavity cancer in xenografted and orthotopic mouse models

Sanjiv

Suman

et al. 2011

Intl Journal of Cancer

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“…13 Those drugs most active are the nitrosoureas, such as carmustine (BCNU) and lomustine (CCNU), in addition to temozolomide (TMZ), procarbazine, cis-retinoic acid, and platinum compounds. 1,2,4,5,[10][11][12]14,17,[23][24][25][26][27] Bevacizumab, with or without irinotecan (CPT-11), has activity in recurrent glioblastoma (GBM), and a small data set exists for activity as well in recurrent anaplastic gliomas. [28][29][30][31][32][33][34] The objective of this single institution retrospective analysis was to observe whether bevacizumab as a single agent, given every 2 weeks, could significantly delay progression in patients with neuroradiographically recurrent 1p19q codeleted AO/AOA as determined by PFS-6.…”

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Bevacizumab for recurrent alkylator‐refractory anaplastic oligodendroglioma

Chamberlain

Johnston

2009

Cancer

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BACKGROUND:A retrospective evaluation of single agent bevacizumab was carried out in adults with recurrent alkylator‐refractory 1p19q codeleted anaplastic oligodendrogliomas (AO) with an objective of determining progression‐free survival (PFS). There is no standard therapy for alkylator‐resistant AO, and hence a need exists for new therapies.METHODS:Twenty‐two patients aged 24 to 60 years with recurrent AO were treated. All patients had previously been treated with surgery, radiotherapy, adjuvant chemotherapy (temozolomide, 17; carmustine wafers, 4; carmustine, 1), and 1 salvage regimen (procarbazine, lomustine, and vincristine, 15; temozolomide, 6; carmustine wafers, 1). Eleven patients underwent repeat surgery. Patients were treated at second recurrence with bevacizumab, once every 2 weeks, defined as a single cycle. Neurological evaluation was performed every 2 weeks, and neuroradiographic assessment was made after the initial 2 cycles of bevacizumab and subsequently after every 4 cycles of bevacizumab.RESULTS:A total of 391 cycles of bevacizumab (median, 14.5 cycles; range, 2‐39 cycles) were administered. Bevacizumab‐related toxicity included fatigue (14 patients; 4 grade 3), leukopenia (9; 1 grade 3), anemia (5; 0 grade 3), hypertension (5; 1 grade 3), deep vein thrombosis (4; 1 grade 3), and wound dehiscence (2; 1 grade 3). Fifteen (68%) patients demonstrated a partial radiographic response, 1 (5.0%) demonstrated stable disease, and 6 (27%) demonstrated progressive disease after 2 cycles of bevacizumab. Time to tumor progression ranged from 1 to 18 months (median, 6.75 months). Survival ranged from 3 to 19 months (median, 8.5 months). Six‐month and 12‐month PFS were 68% and 23%, respectively.CONCLUSIONS:Bevacizumab demonstrated efficacy and acceptable toxicity in this cohort of adults with recurrent 1p19q codeleted alkylator‐refractory AO. Cancer 2009. © 2009 American Cancer Society.

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“…Although malignant gliomas are commonly treated with a combination of radiation and chemotherapy, the majority of tumors recur rapidly after conventional therapy [1,2]. However, response to treatment varies widely, reflecting differences between tumors in their vulnerability to undergoing apoptosis in response to cytotoxic treatment modalities.…”

Section: Introductionmentioning

confidence: 99%

AG490 influences UCN-01-induced cytotoxicity in Glioma cells in a p53-dependent fashion, correlating with effects on BAX cleavage and BAD phosphorylation

2007

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We determined the cytotoxicity of AG490 as a single agent and in combination with 7-OHhydroxystaurosporine (UCN-01) in a panel of malignant human glioma cell lines. Because p53 has important roles in cell cycle checkpoints, it has been anticipated that modulation of checkpoint pathways should sensitize p53-defective cells while sparing the normal cells. Cell proliferation was determined from dose-response curves. AG490 was effective as a cytotoxic agent alone regardless of p53 status. Combining the Chk1 inhibitor UCN-01 dramatically enhanced the response to AG490 in p53 mutated or deleted glioma cells. An opposite effect was noted in p53 wild-type cells, in which UCN-01 and AG490 had antagonist effects on cell proliferation and viability. We found that AG490 enhanced BAD phosphorylation in p53 wild type glioma cells, which appeared to protect against UCN-01 induced cytotoxicity, whereas AG490 enhances UCN-01-induced cytotoxicity in p53-defective cell lines by suppression of BAD phosphorylation, and induction of BAX and PARP cleavage. These observations highlight the potential for genotype-dependent factors to strongly influence response to signaling-targeted therapies in malignant gliomas and the importance of considering such factors in correlative response analyses for these agents.

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Superiority of post-radiotherapy adjuvant chemotherapy with CCNU, procarrazine, and vincristine (PCV) over BCNU for anaplastic gliomas: NCOG 6G61 final report

Cited by 372 publications

References 10 publications

The novel DNA alkylating agent BO‐1090 suppresses the growth of human oral cavity cancer in xenografted and orthotopic mouse models

The novel DNA alkylating agent BO‐1090 suppresses the growth of human oral cavity cancer in xenografted and orthotopic mouse models

Bevacizumab for recurrent alkylator‐refractory anaplastic oligodendroglioma

AG490 influences UCN-01-induced cytotoxicity in Glioma cells in a p53-dependent fashion, correlating with effects on BAX cleavage and BAD phosphorylation

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