Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0029463 (osteosarcoma)
 16,637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Irinotecan (CPT-11) is a semi-synthetic derivative of camptothecin currently in clinical trials. In vitro, CPT-11 presented preferential cytotoxicity toward some solid tumor cells (mouse colon 38 and pancreas 03; human pancreas MIA PaCa-2) as compared to leukemia cells (L1210), whereas SN-38, a metabolite of CPT-11, was not solid tumor selective. In vivo, schedule of administration studies in P388 leukemia and mammary adenocarcinoma 16/C (MA16/C) showed that CPT-11 was not markedly schedule dependent. In order to determine its spectrum of anticancer activity, CPT-11 was evaluated against a variety of mouse and human tumors. The end points used were total log cell kill (Lck) for solid tumors and increase in life span (% ILS) for leukemia. Intravenous CPT-11 was found highly active against both early and advanced stage pancreatic ductal adenocarcinoma 03 (P03), with 60% long-term survivors and 100% complete regressions, respectively. Other responsive tumors included: colon adenocarcinomas 38 and 51 (both 1.0 Lck); MA16/C (3.4 Lck); MA13/C (1.0 Lck); human Calc18 breast adenocarcinoma (2.8 Lck); Glasgow osteogenic sarcoma (1.8 Lck); Lewis lung carcinoma (1.4 Lck); B16 melanoma (1.4 Lck); P388 leukemia (170% ILS) and L1210 leukemia (64% ILS). Of interest, CPT-11 was active against tumors with acquired resistance to vincristine (P388/Vcr), to doxorubicin (P388/Dox) and to docetaxel (Calc18/TXT). CPT-11 was also found highly active after oral administration in mice bearing P03 and MA16/C tumors. Pharmacokinetic evaluations performed i.v. at the highest non-toxic dosage in mice bearing P03 tumors revealed CPT-11 peak plasma concentrations (Cmax) of 8.9 micrograms/ml and a terminal half-life of 0.6 h. The metabolite SN-38 plasma concentrations presented a Cmax of 1.6 micrograms/ml and a terminal half-life of 7.4 h. Although the CPT-11 tumor levels were similar to the plasma concentrations for early time points, drug levels decreased more slowly in the tumor compared to plasma (half-life, 5.0 h). SN-38 tumor levels reached concentrations in the range of 0.32-0.34 micrograms/g and decayed with a half-life of 6.9 h. No significant difference in plasma or tumor pharmacokinetics of either CPT-11 or SN-38 were noted after one or five daily i.v. injections. Overall, these data show that CPT-11 has good activity in experimental models, when administered both by the i.v. and the oral routes. Compared to humans, a similar schedule of administration independence was observed and similar CPT-11 levels could be reached at efficacious dosages although metabolite SN-38 levels were found higher in mice.
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PMID:Experimental antitumor activity and pharmacokinetics of the camptothecin analog irinotecan (CPT-11) in mice. 882 13

Despite improvement in the treatment of osteosarcoma (OS), there are still many patients who cannot benefit from current treatment modalities. This warrants exploration of new treatment options. To that end, we investigated gene-directed enzyme prodrug therapy (GDEPT) with the use of human liver carboxylesterase-2 (CE2) and the anticancer agent CPT-11. CPT-11 is a clinically approved prodrug that needs to be metabolized into the active drug SN-38 by CEs, which occurs rather inefficiently in humans. GDEPT aims at high production of CE2 at the tumor site, resulting in efficient local conversion of CPT-11 into SN-38. Here, we show that OS cells transduced with an adenoviral vector containing the cDNA encoding a secreted form of CE2 (Ad-sCE2) expressed and efficiently secreted CE2. In vitro, transduction of a panel of OS cell lines with Ad-sCE2 resulted in sensitization up to 2800-fold to CPT-11 treatment. Primary OS short-term cultures, derived from patients suffering from a classic high-grade OS, demonstrated increased CPT-11 sensitivity up to 70-fold after transduction with Ad-sCE2 in vitro. When mice bearing s.c. MG-63 OS xenografts were intratumorally injected with Ad-sCE2 and CPT-11, this resulted in a significant difference in time to reach 2000 mm(3) in tumor volume as compared with animals receiving Ad-sCE2 or CPT-11 treatment (P < 0.05). Taken together, these data suggest that OS cells are sensitive for the combination of Ad-sCE2 and CPT-11.
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PMID:Gene-directed enzyme prodrug therapy for osteosarcoma: sensitization to CPT-11 in vitro and in vivo by adenoviral delivery of a gene encoding secreted carboxylesterase-2. 1293 66

Schimke immuno-osseous dysplasia (SIOD) is a multisystemic disorder with prominent skeletal, renal, immunological, and ectodermal abnormalities. It is caused by mutations of SMARCAL1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1), which encodes a DNA stress response protein. To determine the relationship of this function to the SIOD phenotype, we profiled the cancer prevalence in SIOD and assessed if defects of nucleotide excision repair (NER) and nonhomologous end joining (NHEJ), respectively, explained the ectodermal and immunological features of SIOD. Finally, we determined if Smarcal1(del/del) mice had hypersensitivity to irinotecan (CPT-11), etoposide, and hydroxyurea (HU) and whether exposure to these agents induced features of SIOD. Among 71 SIOD patients, three had non-Hodgkin lymphoma (NHL) and one had osteosarcoma. We did not find evidence of defective NER or NHEJ; however, Smarcal1-deficient mice were hypersensitive to several genotoxic agents. Also, CPT-11, etoposide, and HU caused decreased growth and loss of growth plate chondrocytes. These data, which identify an increased prevalence of NHL in SIOD and confirm hypersensitivity to DNA damaging agents in vivo, provide guidance for the management of SIOD patients.
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PMID:SMARCAL1 deficiency predisposes to non-Hodgkin lymphoma and hypersensitivity to genotoxic agents in vivo. 2288 40