Cancer research
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Infection with hepadnaviruses and exposure to dietary aflatoxin are considered major risk factors in the development of hepatocellular carcinoma (HCC) both in humans and in animals. Recently, a broad range of mutations in the p53 tumor suppressor gene has been reported in human HCCs, predominantly from hepatitis B virus carriers in areas with either high or low levels of exposure to dietary aflatoxin. To determine whether p53 mutations are common to HCCs of hosts infected with related hepadnaviruses with and without treatment with aflatoxin, we studied the occurrence of mutations in the p53 gene in HCCs of ground squirrels and woodchucks with history of infection with ground squirrel hepatitis virus (GSHV) and woodchuck hepatitis virus, respectively. ⋯ Mutation was caused by a G to T transversion in the second position of the codon, resulting in the replacement of cysteine with phenylalanine, and was accompanied by a tumor-specific loss of heterozygosity. p53 allelic amino acid variation with sequences coding for aspartic acid or asparagine was present in codon 61 in the variable region of exon 4 in both HCCs and nonneoplastic tissues of ground squirrels. In view of the considerably lower apparent rate of mutations in comparison to human HCCs, we suggest a less important role for aflatoxin in the induction of p53 mutations in HCCs of ground squirrels. Alternatively, etiological factors other than p53 mutations may be of greater significance in the development of HCC in ground squirrels and woodchucks.
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We present a physiological pharmacokinetic model that describes the plasma and cerebrospinal fluid (CSF) concentrations of topotecan [(S)-9-dimethylaminomethyl-10-hydroxyamptothecin hydrochloride, SK&F 104864-A, NSC 609699] following i.v. and intraventricular administrations in monkeys. The model consists of three physical spaces: the CSF, the plasma, and a body compartment. The model incorporates such processes as reversible conversion of topotecan lactone to an inactive hydroxy acid form, microvascular exchange between CSF and plasma, bulk CSF flow, exchange between plasma and body compartments, and elimination of drug from the plasma compartment. ⋯ The forward and reverse rate constants for the lactone-to-hydroxy acid conversion were 1.0 and 0.29 h-1, respectively. Comparison of the clearances (normalized to body surface area) with values reported for mice and humans shows reasonable similarity across species. This pharmacokinetic model may help guide future development and refinement of clinical protocols, especially in the treatment of diseases of the central nervous system.
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A platinum(II) and 3 platinum(IV) ammine/cycloalkylamine homologous series were evaluated for cytotoxicity and biochemical pharmacology in murine leukemia L1210/0, cis-diamminedichloroplatinum(II)- resistant L1210/DDP, and diaminocyclohexaneplatinum-resistant L1210/1,2-diaminocyclohexane (DACH) cells. Within each series, which contained 4 homologues with differing alicyclic (cycloalkyl) ring size (cyclopropane, cyclobutane, cyclopentane, or cyclohexane), cytotoxicity increased with increasing ring size. This appeared to be due to an increase in partition coefficient, and the resulting increase in drug accumulation and intracellular DNA adducts in ascending each of the series. ⋯ The axial acetatoplatinum(IV) and axial hydroxoplatinum(IV) complexes were reduced more slowly, which may explain their lower potency, but not the ability of the higher member to circumvent both cis-diamminedichloroplatinum(II) and trans-1R,2R-1S,2S- diaminocyclohexanetetrachloroplatinum(IV) resistances. Explanation for this will require additional studies. The results have demonstrated high dependencies on ring size of the carrier amine ligand, valence state of platinum, and the nature of the axial ligand for modulation of potency, cross-resistance property, and biochemical pharmacology of ammine/cycloalkylamine complexes.
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Clinical Trial Controlled Clinical Trial
Phase I and pharmacokinetic study of the camptothecin derivative irinotecan, administered on a weekly schedule in cancer patients.
Irinotecan (CPT-11) is a novel water-soluble, semisynthetic derivative of camptothecin, with inhibitory effects on mammalian DNA topoisomerase I, high cytotoxic activity in vitro and anticancer activity in animal models. Fifty-nine patients, with cancer refractory to conventional therapy, were entered in this phase I study, using a weekly schedule administration. A total of 304 weekly doses were administered at dose levels ranging from 50 to 145 mg/m2 (30-90 min i.v. infusion). ⋯ Both CPT-11 and 7-ethyl-10-hydroxycamptothecin areas under the plasma concentration versus time curve correlated significantly with leukoneutropenia and diarrhea. One partial and 4 minor responses were observed at dose levels of 130 and 145 mg/m2. Using this weekly schedule, recommended doses for phase II studies are 100 mg/m2 in high risk patients and 115 mg/m2 in others.
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Castration of rats transplanted with the androgen-sensitive Dunning R3327-PAP prostatic tumor results initially in a reduction of tumor growth, but after some time, some of the tumors start to grow again. The relapsed, androgen-insensitive PAP tumor shows a dedifferentiated morphology. In the present study, we examined whether this androgen-independent tumor regrowth was due to an increased cell proliferation rate or to a reduction of the number of tumor cells dying by apoptosis. ⋯ Tumor growth rate correlated negatively both to the apoptotic index identified by morphological criteria (RS = -0.82; P < 0.0001) and to the apoptotic index identified by in situ end labeling (RS = -0.83; P < 0.0001). The tumor growth rate percentage did not correlate to the mitotic index, and it was negatively correlated (RS = -0.62; P < 0.01) to the number of cells immunostained for proliferating cell nuclear antigen. It is suggested that one initial event during the androgen-independent prostatic tumor regrowth in the PAP relapse model might be a reduction of the number of tumor cells being depleted by apoptosis, rather than an increase of cell proliferation rate.