Studies on drug transport by normal human leukocytes.
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Biomedical subjects
Publications and source records attributed to D Kessel.
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Methotrexate-promoted survival of mice bearing different transplantable leukemias was compared with uptake of the drug by leukemia cells in vitro. A high degree of correlation (r(2) = 0.88) showed that uptake may be a major determinant of the antitumor activity of methotrexate against transplantable mouse leukemias.
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The effects of aminolevulinic acid (ALA)-based photodynamic therapy (PDT) on tumor blood flow are controversial. This study examines the effects of ALA and Photofrin-based PDT on blood flow of Colon-26 tumors implanted in mice as well as the effects of ALA-based PDT on blood flow of human colorectal carcinomas and a carcinoid tumor in situ. Tumors are implanted in both flanks of mice. One tumor of each animal serves as a control. Blood flow is measured using a laser Doppler method. Tumor blood flow in mice not receiving a photosensitizer but treated with three different light fluences (50, 100 and 150 J/cm2) does not differ significantly from blood flow in the untreated tumor in the opposite flank. PDT after ALA administration using the three different light fluences does not significantly affect blood flow. In contrast, PDT after Photofrin administration causes a significant decrease in tumor blood flow with each light fluence, but this change is not as dramatic as reported in other studies. In contrast to mice, six patients who receive ALA prior to surgery all show a decrease in blood flow (mean = 51.8%, p < 0.001) after PDT using 100 J/cm2. Comparison with other published results suggests that it is likely that flow measurement by the laser Doppler method underestimates the effects of PDT on tumor blood flow due to the depth of laser penetration. Nevertheless, the present observations on blood flow suggest that the effects of ALA-based PDT on adenocarcinomas of the colon and rectum as well as an intra-abdominal carcinoid tumor in humans are more pronounced than would be predicated by some animal studies.
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Drug resistance has complicated chemotherapy of neoplastic disease since the early beginnings of the field. Successful use of drug therapy requires that tumor cells be more drug-responsive than the tissue of origin. This can occur with rapidly-dividing tumors which will be highly-responsive to drugs toxic in the S-phase of the cell cycle. Another drug sensitive population will consist of neoplastic cells unable to repair drug-induced damage which can be repaired by normal host cells. Even if one of these conditions is initially found, mutational events leading to drug resistance often occur. The most thoroughly explored mode of drug resistance involves MDR (multidrug resistance), an outward transport system which limits penetration of a variety of cytotoxic agents into the cytoplasm and nucleus. MDR is expressed by many normal cell types, and attempts at MDR circumvention appear to lead to new modes of host toxicity. It appears that new directions in cancer therapy will be needed to yield responses in the common slow-growing tumors which tend to be inherently drug-resistant.