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P Workman

Publications and source records attributed to P Workman.

243 records · Page 14Linked to original sources
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Non-invasive MRS in new anticancer drug development.

In the rational development of anticancer drugs it is important to employ all the available pharmacological information. Early clinical trials provide an opportunity for hypothesis testing. MRS techniques have the potential to provide valuable data on the preclinical and clinical pharmacokinetics and pharmacodynamics of drugs non-invasively. Here we illustrate advantages and pitfalls of MRS using studies of two fluorine-containing cancer drugs: a beta,beta-difluoro analogue of the alkylating agent chlorambucil and a fluorinated derivative of the nitroimidazole misonidazole, Ro 07-0741. Limitations include signal quenching via protein binding and inadequate sensitivity for more potent drugs like beta,beta-difluorochlorambucil; but fluoromisonidazole was shown to accumulate in tumours and shows promise as a chemical probe for tumour hypoxia, detectable by 19F MRS.

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The pharmacokinetics in mice and dogs of nitroimidazole radiosensitizers and chemosensitizers more lipophilic than misonidazole.

We have examined the pharmacokinetic properties of nitroimidazole radiosensitizers and chemosensitizers more lipophilic than misonidazole (MISO). In dogs, 2 analogues showed comparable peak plasma concentrations with considerably shorter half-lives (t1/2) and reduced areas under curves (AUC). Benznidazole (Ro 07-1051) had a much longer t1/2, a higher AUC, and somewhat higher peak concentrations. In mice tumor/plasma, brain/plasma, and tumor/brain ratios were generally similar to MISO, as was penetration of brain and peripheral nerve by benznidazole in dogs. Selection of lipophilic analogues with appropriate pharmacokinetic properties may facilitate accommodation of the potentially different requirements for improved radiosensitization or chemosensitization.

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The effect of radiosensitizer pretreatment on the response of the RIF-1 mouse sarcoma to cytotoxic drugs.

We have studied the effect of misonidazole (MISO) or metronidazole (MET) pretreatment upon the response of the RIF-1 mouse tumor to cytotoxic drugs. The response to melphalan was unchanged and that to cyclophosphamide only marginally affected by pretreatment. For CCNU and chlorambucil, the dose modifying factors (DMFs) were 1.3 and 2.0 respectively for MISO and 1.0 and 1.4 respectively for MET. The acute LD50 of CCNU was reduced by MISO (DMF approximately 1.2) but depression of white blood cells was unchanged. For chlorambucil, modification of normal tissue response was similar to that seen in the tumor. Other radiosensitizers (Ro 07-1902, Benznidazole) were more effective than MISO in enhancing tumor response to chlorambucil. Compounds which do not contain nitro groups, and which are not electron-affinic, (imidazole, SKF 525A) can also produce the effect.

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Enhancement by electron-affinic agents of the therapeutic effects of cytotoxic agents against the KHT tumor: structure-activity relationships.

We have studied the effectiveness of various electron-affinic and other modifying agents on the in vivo response of the KHT sarcoma to various cytotoxic agents. Misonidazole (MISO) showed good enhancement with CCNU, methyl-CCNU, BCNU and chlorambucil (CHL), a small enhancement with cyclophosphamide (CYC), but none with melphalan or HN2. With CYC a further small enhancement was obtained with a multiple-dose pretreatment, but host toxicity was also increased. Lipophilicity was more important than electron-affinity for CCNU enhancement. Several lipophilic analogues (e.g. benznidazole and Ro 07-1902) gave enhancements superior to MISO, whereas hydrophilic analogues were inferior. Similar results were obtained with CHL. Enhancement of CCNU response was seen with the nitrofuran, nitrofurantoin, and the quinone, anthraquinone sulphonate. The non-electron affinic compound imidazole gave enhancement with CHI, but not with CCNU. The inhibitor of drug-metabolizing enzymes SKF 525A gave excellent enhancement with both CHL and CCNU.

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PubMedDate not supplied

Effects of cimetidine, antipyrine, and pregnenolone carbonitrile on misonidazole pharmacokinetics.

We investigated the effects of cimetidine, antipyrine, and pregnenolone carbonitrile on the pharmacokinetics of misonidazole (MISO) in mice. antipyrine did not induce MISO demethylation. Considerable induction was seen with pregnenolone carbonitrile, but it was not superior to phenobarbital. Cimetidine inhibited MISO demethylation and increased its half-life and area under the curve. We suggest that patients receiving cimetidine and MISO have their MISO pharmacokinetics carefully monitored.

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