Development of a Panel of 15 Human Ovarian Cancer Xenografts for Drug Screening and Determination of the Role of the Glutathione Detoxification System
Geertruida M. KolfschotenHerbert M. PinedoP SchefferHennie M.M. SchlüperCaroline A.M. ErkelensEpie Boven
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Growth inhibition
The mechanism of doxorubicin is compared with that of doxazolidine, a doxorubicin−formaldehyde conjugate. The IC50 for growth inhibition of 67 human cancer cell lines, but not cardiomyocytes, is 32-fold lower with doxazolidine than with doxorubicin. Growth inhibition by doxazolidine correlates better with growth inhibition by DNA cross-linking agents than with growth inhibition by doxorubicin. Doxorubicin induces G2/M arrest in HCT-116 colon cancer cells and HL-60 leukemia cells through a well-documented topoisomerase II dependent mechanism. Doxazolidine fails to induce a G2/M arrest in HCT-116 cells but induces apoptosis 4-fold better than doxorubicin. The IC50 for doxazolidine growth inhibition of HL-60/MX2 cells, a topoisomerase II deficient derivative of HL-60 cells, is 1420-fold lower than the IC50 for doxorubicin, and doxazolidine induces apoptosis 15-fold better. Further, doxazolidine has little effect in a topoisomerase II activity assay. These data indicate that doxorubicin and doxazolidine induce apoptosis via different mechanisms and doxazolidine cytotoxicity is topoisomerase II independent.
Growth inhibition
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A comparative study of two combination chemotherapy regimens including (2'' R)-4'-O-Tetrahydropyranyladriamycin (THP) or Adriamycin (ADR) was performed to evaluate its efficacy and safety in advanced and recurrent breast cancer. In this study 64 patients were evaluated, and the response rate was 35.1% (13 of 37 patients) in group A (combination chemotherapy of THP, 5-Fluorouracil and cyclophosphamide), and 29.6% (8 of 27 patients) in group B (ADR, 5-Fluorouracil and cyclophosphamide). There was no statistically significant difference between the response rates of the two groups. As for safety, that of group A was significantly superior to group B for alopecia while that of group A tended to be lower than group B for anorexia. From the above results, THP in combination with cyclophosphamide and 5-Fluorouracil is comparable to ADR in efficacy and can be regarded as having better safety than ADR for the treatment of breast cancer.
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저자들은 융모성질환의 화학치료에 있어서 methotrexate 치료도중 문제가 될 수 있는 약제의 독성을 줄이고, 내성을 방지하기 위하여 leucovorin rescue를 주는 적절한 시기 및 용량을 결정하고자 methotrexate 포화검사를 시행하여 다음과 같은 결론을 얻었다. 1. Methotrexate혈중치는 methotrexate의 정맥내 주사후 30분에 최고 농도에 달하며, 그 반감기는 5.04±2.05 시간이었다. 2. Methotrexate정맥내 주사후 24시간후와 28시간후에 30mg이 folic acid를 줄때 혈중 methotrexate 평균농도는 24시간후에 50μmole/liter였고, 48시간후에 0.32μmole/liter이었다. 3. Methotrexate치료중 약제의 독성과 반감기를 비교해 본 결과 반감기가 평균보다 긴 경우 그 약제의 독성이 강한 것으로 보이나 통계적인 유효성은 없는 것으로 나타났다. Methotrexate 치료중 약제의 족성과 methotrexate 정맥주사후 48시간의 methotrexate 혈중치를 비교해 본 결과 간독성에 있어서는 유의한 차이가 없으나, 혈액학적 독성에 있어서는 methotrexate 혈중치가 평균보다 높은군이 낮은군에 비해 강한 독성이 나타났다. 이상과 같이 저자들은 methotrexate의 항암화학 요법에 있어서 강한 약제의 독성을 나타낼 가능성이 있는 환자를 알아내는데에 methotrexate 포화검사가 유용하게 쓰일 수 있으며, 약제의 독성을 나타낼 가능성이 큰 환자에 있어서는 methotrexate 혈중농도를 측정하여야 그에 따른 leucovorin rescue를 시행하여야 한다고 결론지었다.
Antifolate
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The interaction of methotrexate and/or cyclophosphamide with the pharmacokinetics of 5-fluorouracil (5-FU) was studied in tumor-bearing WAG/Rij rats. Four groups were formed including treatment with single-agent 5-FU (eight rats); 5-FU plus methotrexate (11 rats); 5-FU plus cyclophosphamide (12 rats); and 5-FU, cyclophosphamide, and methotrexate (13 rats). The area-under-the-plasma-concentration/time curve, total-body clearance, elimination half-life, mean residence time, and steady-state volume of distribution were computed and compared. The mean residence time and elimination half-life of 5-FU increased when methotrexate was included in the combination. The increase was significant (P less than 0.05) for 5-FU, cyclophosphamide, and methotrexate versus 5-FU and cyclophosphamide.
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The antitumor effects of methotrexate with 5-fluorouracil against the Sarcoma 180 mouse tumor model were found to be schedule dependent. Pretreatment of tumor-bearing animals with methotrexate significantly enhanced the antitumor activity of the combination relative to simultaneous treatment or to those with methotrexate following 5-fluorouracil. These studies indirectly support the hypothesis that methotrexate pretreatment with 5-fluorouracil is synergistic by increasing the amount of thymidylate synthetase bound to the active metabolite of 5-fluorouracil.
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In tumor-bearing WAG/Rij rats the interaction of cyclophosphamide and/or 5-fluorouracil (5-FU) with methotrexate as manifested at the pharmacokinetic level was studied. Four groups were formed of at least ten animals. The control group, which received single-agent methotrexate, was compared with groups that received methotrexate plus cyclophosphamide, methotrexate plus 5-FU, and methotrexate plus cyclophosphamide plus 5-FU. There appeared to be an increase of 40% in the clearance of methotrexate by the triple combination. Cyclophosphamide especially diminished the terminal part of the concentration-time curve of methotrexate.
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The sequential treatment of mice with advanced leukemia L1210 employing a single injection of 2-chloro-4′,4″-di-2-imidazolin-2-ylterephthalanilide, dihydrochloride (NSC-38280) or cyclophosphamide followed by multiple treatment with methotrexate (MTX) was examined. Mice that received a single injection of NSC-38280 or cyclophosphamide followed by MTX given daily or every 4 days displayed more extensive increases in median survival time than did mice receiving MTX alone on a daily or every-4-day treatment schedule. An initial treatment with either NSC-38280 or cyclophosphamide followed by daily MTX was approximately twice as effective as daily MTX alone, whereas NSC-38280 or cyclophosphamide followed by MTX every 4 days was 3–4 times more effective than MTX alone every 4 days.
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