Cancer chemotherapy and pharmacology
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Cancer Chemother. Pharmacol. · Jan 1997
Biodistribution of an antibody-enzyme conjugate for antibody-directed enzyme prodrug therapy in nude mice bearing a human colon adenocarcinoma xenograft.
The enzyme carboxypeptidase G2 (CPG2) can be targeted to tumors by antibodies and used to activate prodrugs in a treatment called antibody-directed enzyme prodrug therapy (ADEPT). Different doses of CPG2 conjugated to the anti-CEA antibody A5B7 were administered i.v. to nude mice bearing the LS174T human colon adenocarcinoma xenograft, and the biodistribution of conjugate activity 48 and 72 h later was determined using a novel high-performance liquid chromatography (HPLC) method. Conjugate doses of 2,500 and 625 U/kg gave tumor enzyme levels of 0.5-0.6 U/g. ⋯ This conjugate dose also gave the greatest tumor:tissue ratios in all other tissues examined. After 72 h the tumor:colon ratio was 105, whereas the tumor:kidney ratio was 36. In ADEPT, to obtain maximal tumor damage to LS174T xenografts in nude mice with minimal systemic toxicity using the A5B7-CPG2 conjugate, prodrug should therefore be administered at least 72 h after a conjugate dose of 625 U/kg.
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Cancer Chemother. Pharmacol. · Jan 1997
Comparative StudyIn vitro phase II comparison of the cytotoxicity of a novel platinum analog, nedaplatin (254-S), with that of cisplatin and carboplatin against fresh, human ovarian cancers.
To compare the in vitro cytotoxicity of nedaplatin, an investigational platinum analog, with that of the standard platinum agents, cisplatin and carboplatin, against fresh human, epithelial ovarian cancers. ⋯ Nedaplatin was associated with cytotoxicity similar to cisplatin and carboplatin in this study. Although nedaplatin appears to be crossresistant with cisplatin, its high rate of in vitro cytotoxicity, relative lack of neurotoxicity and nephrotoxicity, and large in vivo biovailability establish nedaplatin as a promising platinum analog for further clinical development as a salvage and primary chemotherapeutic agent for patients with advanced ovarian cancer.
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Cancer Chemother. Pharmacol. · Jan 1997
A sequential Bayesian algorithm for dose individualisation of carboplatin.
Carboplatin is associated with significantly less nephrotoxicity and neurotoxicity than is cisplatin. The dose-limiting toxicity of carboplatin is myelotoxicity. A number of dosing methods have been described that allow a value for the area under the concentration-time curve to be targeted on the basis of the patient's renal function. ⋯ To our knowledge, this is the first sequential design that has been used for dose individualisation of chemotherapy. The program is specific for carboplatin and operates independently of commercially available Bayesian software. Doses predicted by this program are being tested prospectively against conventional dosing methods.
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Cancer Chemother. Pharmacol. · Jan 1997
Comparative StudyOptimizing interstitial delivery of BCNU from controlled release polymers for the treatment of brain tumors.
Two approaches for improving the interstitial administration of carmustine (BCNU) using 3.8% loaded poly(carboxyphenoxypropane-sebacic acid), an implantable biodegradable anhydride which significantly prolongs survival in patients with recurrent malignant gliomas, were evaluated. First, increasing the ratio of carboxyphenoxypropane (CPP) to sebacic acid (SA) in the polymer increases its hydrolytic stability, thus prolonging its half-life in vivo, and extending the period of drug release. A second approach is to increase the dose of drug loaded into the polymer. ⋯ The 20% BCNU-loaded 20:80 polymer achieved the best balance of toxicity and antitumor efficacy, yielding a 75% long-term survival rate. Further evaluation of this polymer in monkeys suggests that it might be used with acceptable toxicity. This study establishes that a dose-escalation strategy for improving BCNU controlled-release polymers is more effective than adjusting the ratio of CPP to SA to prolong drug release.
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Cancer Chemother. Pharmacol. · Jan 1997
Characterization of cellular accumulation and toxicity of illudin S in sensitive and nonsensitive tumor cells.
Illudins are novel low molecular weight natural products cytotoxic to human tumor cells in vitro. Illudin-derived analogs are effective against experimental human cancers nonresponsive to conventional anticancer agents. It is not known why some illudin analogs are more efficacious in vitro and in vivo than other analogs. ⋯ The number of intracellular illudin S molecules required to kill 50% of cells of different tumor cell lines varied from 78000 to 1114000 molecules per cell and was correlated with the 2-h IC50 value determined using a colony-forming assay. Illudin S was cytotoxic to a variety of multidrug-resistant tumor cell lines regardless of whether resistance was mediated by gp170/mdrl, gp180/MRP, GSHTR-pi, topoisomerase I, topoisomerase II, increased DNA repair capacity, or alterations in intracellular thiol content. Information obtained in this study could be used to design clinical phase I trials and to develop analogs with improved therapeutic indexes.