The Experts below are selected from a list of 591 Experts worldwide ranked by ideXlab platform
Henry S Friedman - One of the best experts on this subject based on the ideXlab platform.
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schedule dependent activity of temozolomide plus cpt 11 against a human central nervous system tumor derived xenograft
Clinical Cancer Research, 2000Co-Authors: Vikas J Patel, Gertrude B Elion, Peter J Houghton, Stephen T Keir, Stewart P Johnson, Darell D Bigner, Henry S FriedmanAbstract:Temozolomide, an imidazole tetrazinone, and CPT-11, a Camptothecin Derivative, have previously been shown to have anti-central nervous system tumor activity in laboratory and clinical studies. The current experiments were designed to evaluate the activity of temozolomide plus CPT-11 against a malignant glioma-derived xenograft, D-54 MG, growing s.c. in athymic nude mice. The initial schedule of i.p. drug administration was temozolomide at 0.1 LD10 on day 1 and CPT-11 at 0.1 LD10 on days 1-5 and 8-14. The combination of these two agents produced greater than additive activity against D-54 MG. This enhanced activity was maintained when the initial administration of CPT-11 was delayed to day 3 or day 5. However, when CPT-11 was administered first on day 1 using 0.5 LD10 (for the single dose schedule) followed by temozolomide (0.1 LD10) 5 h, 3 days, or 5 days later, the enhancement of activity was substantially reduced. These results demonstrate that the combination of temozolomide plus CPT-11 displays a schedule-dependent enhancement of antitumor activity, suggest a mechanistic explanation for the enhanced activity, and provide the rationale for a Phase I trial of this regimen.
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therapeutic efficacy of the topoisomerase i inhibitor 7 ethyl 10 4 1 piperidino 1 piperidino carbonyloxy Camptothecin against pediatric and adult central nervous system tumor xenografts
Cancer Chemotherapy and Pharmacology, 1996Co-Authors: Bradley C Hare, Gertrude B Elion, Peter J Houghton, Stephen T Keir, Darell D Bigner, Susan Marcelli, Janet A Houghton, Henry S FriedmanAbstract:Therapy of patients with malignant central nervous system tumors is frequently unsuccessful, reflecting limitations of current surgical, radiotherapeutic, and pharmacotherapeutic treatments. The Camptothecin Derivative irinotecan (CPT-11) has been shown to possess antitumor activity in phase II trials for patients with carcinoma of the lung, cervix, ovary, colon, or rectum and for patients with non-Hodgkin’s lymphoma. The current study was designed to test the efficacy of the drug against a panel of human tumor xenografts derived from adult and pediatric central nervous system malignancies. Tumors included childhood high-grade gliomas (D-212 MG, D-456 MG), adult high-grade gliomas (D-54 MG, D-245 MG), medulloblastomas (D341 Med, D487 Med), ependymomas (D528 EP, D612 EP), and a rhabdomyosarcoma (TE-671), as well as sublines with demonstrated resistance to busulfan (D-456 MG (BR)), cyclophosphamide (TE-671 CR), procarbazine (D-245 MG (PR)) or melphalan (TE-671 MR), growing subcutaneously and intracranially in athymic nude mice. In replicate experiments, CPT-11 was given at a dosage of 40 mg/kg per dose via intraperitoneal injection in 10% dimethylsulfoxide on days 1–5 and 8–12, which is the dosage lethal to 10% of treated animals. CPT-11 produced statistically significant (P<0.001) growth delays in all subcutaneous xenografts tested, including those resistant to busulfan, cyclophosphamide, procarbazine, and melphalan, with growth delays ranging from 21.3 days in D487 Med to 90+ days in several tumor lines. Further, tumor regression was evident in every treated animal bearing a subcutaneous tumor, with some xenografts yielding complete tumor regression. Statistically significant (P<0.001) increases in survival were demonstrated in the two intracranial xenografts – D341 EP (73.0% increase) and D-456 MG (114.2% increase) – treated with CPT-11. These studies demonstrate that, of over 40 drugs evaluated in this laboratory, CPT-11 is the most active against central nervous system xenografts and should be advanced to clinical trial as soon as possible.
Tetsuya Kamataki - One of the best experts on this subject based on the ideXlab platform.
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involvement of β glucuronidase in intestinal microflora in the intestinal toxicity of the antitumor Camptothecin Derivative irinotecan hydrochloride cpt 11 in rats
Cancer Research, 1996Co-Authors: Kiyoshi Takasuna, Takehiro Hagiwara, Masaaki Hirohashi, Michiyuki Kato, Mamoru Nomura, Eiichi Nagai, Tsuyoshi Yokoi, Tetsuya KamatakiAbstract:Abstract Irinotecan hydrochloride (CPT-11), an antitumor Camptothecin Derivative, causes severe forms of diarrhea clinically. We characterized CPT-11-induced diarrhea histologically and enzymologically and assessed the relationships between intestinal toxicity and the activity of the enzymes that play a key role in the major metabolic pathway of CPT-11 in rats. CPT-11 (60 mg/kg i.v. for 4 days) induced intestinal toxicity characterized by severe chronic diarrhea, loss of body weight, and anorexia. Histological damage was most severe in the cecum. The segmental difference in the degree of the damage showed good correlation with the β-glucuronidase activity in the contents of the lumen in each case, but not with the intestinal tissue carboxylesterase activity, which converts CPT-11 to its active form (7-ethyl-10-hydroxyCamptothecin). Inhibition of the β-glucuronidase activity in the intestinal microflora by antibiotics (1 mg penicillin and 2 mg streptomycin per ml of drinking water) markedly ameliorated the diarrhea and reduced cecal damage. Analysis of CPT-11 and its metabolites in the feces indicated that antibiotics completely inhibited the deconjugation of the glucuronic conjugate of 7-ethyl-10-hydroxyCamptothecin by β-glucuronidase. It is suggested that CPT-11-induced diarrhea would be attributable to the damage to the cecum, and that the inhibition of the β-glucuronidase activity in the intestinal microflora is a major protective effect of antibiotics.
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involvement of beta glucuronidase in intestinal microflora in the intestinal toxicity of the antitumor Camptothecin Derivative irinotecan hydrochloride cpt 11 in rats
Cancer Research, 1996Co-Authors: Kiyoshi Takasuna, Takehiro Hagiwara, Masaaki Hirohashi, Michiyuki Kato, Mamoru Nomura, Eiichi Nagai, Tsuyoshi Yokoi, Tetsuya KamatakiAbstract:Irinotecan hydrochloride (CPT-11), an antitumor Camptothecin Derivative, causes severe forms of diarrhea clinically. We characterized CPT-11-induced diarrhea histologically and enzymologically and assessed the relationships between intestinal toxicity and the activity of the enzymes that play a key role in the major metabolic pathway of CPT-11 in rats. CPT-11 (60 mg/kg i.v. for 4 days) induced intestinal toxicity characterized by severe chronic diarrhea, loss of body weight, and anorexia. Histological damage was most severe in the cecum. The segmental difference in the degree of the damage showed good correlation with the beta-glucuronidase activity in the contents of the lumen in each case, but not with the intestinal tissue carboxylesterase activity, which converts CPT-11 to its active form (7-ethyl-10-hydroxyCamptothecin). Inhibition of the beta-glucuronidase activity in the intestinal microflora by antibiotics (1 mg penicillin and 2 mg streptomycin per ml of drinking water) markedly ameliorated the diarrhea and reduced cecal damage. Analysis of CPT-11 and its metabolites in the feces indicated that antibiotics completely inhibited the deconjugation of the glucuronic conjugate of 7-ethyl-10-hydroxyCamptothecin by beta-glucuronidase. It is suggested that CPT-11-induced diarrhea would be attributable to the damage to the cecum, and that the inhibition of the beta-glucuronidase activity in the intestinal microflora is a major protective effect of antibiotics.
Scott C Jeffrey - One of the best experts on this subject based on the ideXlab platform.
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abstract 2889 sgn cd30c a new cd30 directed Camptothecin antibody drug conjugate adc shows strong anti tumor activity and superior tolerability in preclinical studies
Cancer Research, 2020Co-Authors: Maureen Ryan, Ryan Lyski, Lauren Bou, Steven Jin, Jessica K Simmons, Peter D Senter, David W Meyer, Dennis Benjamin, Scott C JeffreyAbstract:SGN-CD30C, a new CD30-directed ADC, utilizes a potent Camptothecin Derivative as the cytotoxic payload. SGN-CD30C targets the same antigen as brentuximab vedotin (BV), though the payload has a different mechanism of action, namely inhibiting topoisomerase I rather than disrupting microtubules. Unlike monomethyl auristatin E, Camptothecin-based therapies do not cause peripheral neuropathy clinically, suggesting that SGN-CD30C may have the potential to avoid one of the most common adverse events associated with BV. In preclinical studies, SGN-CD30C demonstrated strong monotherapy activity, inducing durable tumor regressions in multiple lymphoma models and eliciting cures in a BV-resistant tumor model. Furthermore, bystander killing of antigen-negative tumor cells, which is thought to be an important attribute of BV, was confirmed in vivo using CD30-heterogeneous tumors. SGN-CD30C was well-tolerated in non-human primate (NHP) toxicology studies and demonstrated ~6-fold higher maximum tolerated dose (MTD) when compared to BV. The primary toxicity for SGN-CD30C in NHP studies was anemia due primarily to bone marrow suppression of erythropoiesis. SGN-CD30C had no effect on neutrophil counts and caused only minimal to mild decreases in platelets. The lack of significant neutropenia seen with SGN-CD30C contrasts with BV, indicating the two antibody-drug conjugates may have non-overlapping dose limiting toxicities. We theorized using a reduced dose of BV in combination with SGN-CD30C could provide a dual mechanism of action to retain or enhance anti-tumor activity while decreasing the incidence of non-overlapping toxicities (i.e. peripheral neuropathy). To test this hypothesis preclinically, we evaluated the anti-tumor activity of BV and SGN-CD30C at sub-curative doses in a Karpas-299 xenograft model. The results show the combination of SGN-CD30C + BV generated a higher number of durable CRs compared to the equivalent monotherapy doses, thereby confirming strong anti-tumor activity by using a lower dose of each ADC in combination. In summary, our data show SGN-CD30C is a compelling therapeutic candidate for CD30-positive malignancies. The strong anti-tumor activity and superior tolerability suggest SGN-CD30C has a favorable therapeutic window. Furthermore, the distinct mechanism of action and non-overlapping toxicity profile offers the potential to combine SGN-CD30C with BV for enhanced risk/benefit. Citation Format: Maureen Ryan, Ryan Lyski, Lauren Bou, David Meyer, Steven Jin, Jessica Simmons, Dennis Benjamin, Peter Senter, Scott Jeffrey. SGN-CD30C, a new CD30-directed Camptothecin antibody-drug conjugate (ADC), shows strong anti-tumor activity and superior tolerability in preclinical studies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2889.
Kiyoshi Takasuna - One of the best experts on this subject based on the ideXlab platform.
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involvement of β glucuronidase in intestinal microflora in the intestinal toxicity of the antitumor Camptothecin Derivative irinotecan hydrochloride cpt 11 in rats
Cancer Research, 1996Co-Authors: Kiyoshi Takasuna, Takehiro Hagiwara, Masaaki Hirohashi, Michiyuki Kato, Mamoru Nomura, Eiichi Nagai, Tsuyoshi Yokoi, Tetsuya KamatakiAbstract:Abstract Irinotecan hydrochloride (CPT-11), an antitumor Camptothecin Derivative, causes severe forms of diarrhea clinically. We characterized CPT-11-induced diarrhea histologically and enzymologically and assessed the relationships between intestinal toxicity and the activity of the enzymes that play a key role in the major metabolic pathway of CPT-11 in rats. CPT-11 (60 mg/kg i.v. for 4 days) induced intestinal toxicity characterized by severe chronic diarrhea, loss of body weight, and anorexia. Histological damage was most severe in the cecum. The segmental difference in the degree of the damage showed good correlation with the β-glucuronidase activity in the contents of the lumen in each case, but not with the intestinal tissue carboxylesterase activity, which converts CPT-11 to its active form (7-ethyl-10-hydroxyCamptothecin). Inhibition of the β-glucuronidase activity in the intestinal microflora by antibiotics (1 mg penicillin and 2 mg streptomycin per ml of drinking water) markedly ameliorated the diarrhea and reduced cecal damage. Analysis of CPT-11 and its metabolites in the feces indicated that antibiotics completely inhibited the deconjugation of the glucuronic conjugate of 7-ethyl-10-hydroxyCamptothecin by β-glucuronidase. It is suggested that CPT-11-induced diarrhea would be attributable to the damage to the cecum, and that the inhibition of the β-glucuronidase activity in the intestinal microflora is a major protective effect of antibiotics.
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involvement of beta glucuronidase in intestinal microflora in the intestinal toxicity of the antitumor Camptothecin Derivative irinotecan hydrochloride cpt 11 in rats
Cancer Research, 1996Co-Authors: Kiyoshi Takasuna, Takehiro Hagiwara, Masaaki Hirohashi, Michiyuki Kato, Mamoru Nomura, Eiichi Nagai, Tsuyoshi Yokoi, Tetsuya KamatakiAbstract:Irinotecan hydrochloride (CPT-11), an antitumor Camptothecin Derivative, causes severe forms of diarrhea clinically. We characterized CPT-11-induced diarrhea histologically and enzymologically and assessed the relationships between intestinal toxicity and the activity of the enzymes that play a key role in the major metabolic pathway of CPT-11 in rats. CPT-11 (60 mg/kg i.v. for 4 days) induced intestinal toxicity characterized by severe chronic diarrhea, loss of body weight, and anorexia. Histological damage was most severe in the cecum. The segmental difference in the degree of the damage showed good correlation with the beta-glucuronidase activity in the contents of the lumen in each case, but not with the intestinal tissue carboxylesterase activity, which converts CPT-11 to its active form (7-ethyl-10-hydroxyCamptothecin). Inhibition of the beta-glucuronidase activity in the intestinal microflora by antibiotics (1 mg penicillin and 2 mg streptomycin per ml of drinking water) markedly ameliorated the diarrhea and reduced cecal damage. Analysis of CPT-11 and its metabolites in the feces indicated that antibiotics completely inhibited the deconjugation of the glucuronic conjugate of 7-ethyl-10-hydroxyCamptothecin by beta-glucuronidase. It is suggested that CPT-11-induced diarrhea would be attributable to the damage to the cecum, and that the inhibition of the beta-glucuronidase activity in the intestinal microflora is a major protective effect of antibiotics.
Peter J Houghton - One of the best experts on this subject based on the ideXlab platform.
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schedule dependent activity of temozolomide plus cpt 11 against a human central nervous system tumor derived xenograft
Clinical Cancer Research, 2000Co-Authors: Vikas J Patel, Gertrude B Elion, Peter J Houghton, Stephen T Keir, Stewart P Johnson, Darell D Bigner, Henry S FriedmanAbstract:Temozolomide, an imidazole tetrazinone, and CPT-11, a Camptothecin Derivative, have previously been shown to have anti-central nervous system tumor activity in laboratory and clinical studies. The current experiments were designed to evaluate the activity of temozolomide plus CPT-11 against a malignant glioma-derived xenograft, D-54 MG, growing s.c. in athymic nude mice. The initial schedule of i.p. drug administration was temozolomide at 0.1 LD10 on day 1 and CPT-11 at 0.1 LD10 on days 1-5 and 8-14. The combination of these two agents produced greater than additive activity against D-54 MG. This enhanced activity was maintained when the initial administration of CPT-11 was delayed to day 3 or day 5. However, when CPT-11 was administered first on day 1 using 0.5 LD10 (for the single dose schedule) followed by temozolomide (0.1 LD10) 5 h, 3 days, or 5 days later, the enhancement of activity was substantially reduced. These results demonstrate that the combination of temozolomide plus CPT-11 displays a schedule-dependent enhancement of antitumor activity, suggest a mechanistic explanation for the enhanced activity, and provide the rationale for a Phase I trial of this regimen.
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therapeutic efficacy of the topoisomerase i inhibitor 7 ethyl 10 4 1 piperidino 1 piperidino carbonyloxy Camptothecin against pediatric and adult central nervous system tumor xenografts
Cancer Chemotherapy and Pharmacology, 1996Co-Authors: Bradley C Hare, Gertrude B Elion, Peter J Houghton, Stephen T Keir, Darell D Bigner, Susan Marcelli, Janet A Houghton, Henry S FriedmanAbstract:Therapy of patients with malignant central nervous system tumors is frequently unsuccessful, reflecting limitations of current surgical, radiotherapeutic, and pharmacotherapeutic treatments. The Camptothecin Derivative irinotecan (CPT-11) has been shown to possess antitumor activity in phase II trials for patients with carcinoma of the lung, cervix, ovary, colon, or rectum and for patients with non-Hodgkin’s lymphoma. The current study was designed to test the efficacy of the drug against a panel of human tumor xenografts derived from adult and pediatric central nervous system malignancies. Tumors included childhood high-grade gliomas (D-212 MG, D-456 MG), adult high-grade gliomas (D-54 MG, D-245 MG), medulloblastomas (D341 Med, D487 Med), ependymomas (D528 EP, D612 EP), and a rhabdomyosarcoma (TE-671), as well as sublines with demonstrated resistance to busulfan (D-456 MG (BR)), cyclophosphamide (TE-671 CR), procarbazine (D-245 MG (PR)) or melphalan (TE-671 MR), growing subcutaneously and intracranially in athymic nude mice. In replicate experiments, CPT-11 was given at a dosage of 40 mg/kg per dose via intraperitoneal injection in 10% dimethylsulfoxide on days 1–5 and 8–12, which is the dosage lethal to 10% of treated animals. CPT-11 produced statistically significant (P<0.001) growth delays in all subcutaneous xenografts tested, including those resistant to busulfan, cyclophosphamide, procarbazine, and melphalan, with growth delays ranging from 21.3 days in D487 Med to 90+ days in several tumor lines. Further, tumor regression was evident in every treated animal bearing a subcutaneous tumor, with some xenografts yielding complete tumor regression. Statistically significant (P<0.001) increases in survival were demonstrated in the two intracranial xenografts – D341 EP (73.0% increase) and D-456 MG (114.2% increase) – treated with CPT-11. These studies demonstrate that, of over 40 drugs evaluated in this laboratory, CPT-11 is the most active against central nervous system xenografts and should be advanced to clinical trial as soon as possible.