Calmodulin inhibitor trifluoperazine in combination with doxorubicin induces the selection of tumour cells with the multidrug resistant phenotype.

Trifluoperazine (TFP) is effective in modulating DNA damage/repair in doxorubicin (DOX) treated cells. In the present study we have characterised the resistance phenotype of parental sensitive L1210 mouse leukaemia cells (L1210/S) adapted to grow in the presence of 0.017 microns DOX+5 microM TFP (L1210/DT). Although with prolonged exposure, 0.017 microM DOX alone produced < 35% cell kill in L1210/S cells, similar cytotoxicity was achieved at 0.43 microM DOX in L1210/S cells selected in the presence of 0.017 microM DOX+5 microM TFP. L1210/DT cells were > 30-fold resistant to DOX following a 3 h drug exposure in a soft agar colony assay. In contrast, DOX sensitivity in cells adapted to grow in 5 microM TFP alone was comparable to L1210/S cells. Resistance to other inhibitors of topoisomerase II in L1210/DT cells was > 30-fold to etoposide and > 6-fold to amsacrine. The levels of the 170 kDa and 180 kDa isoforms of topoisomerase II in an immunoblot were comparable between the L1210/S and L1210/DT cells. Cross resistance to vincristine in the L1210/DT cells was accompanied by the overexpression of plasma membrane P-glycoprotein. Although a 1.5-2-fold decrease in accumulation of etoposide and DOX was observed in the L1210/DT cells, drug levels for equivalent DNA damage in the alkaline elution assay were > 5-fold higher in the L1210/DT versus L1210/S cells. No abrogation in the modulating effects of TFP on DOX, VP-16 or amsacrine induced cytotoxicity was apparent in the L1210/DT cells. Results suggest that: (a) TFP in combination with low concentrations DOX can induce the selection of cells with the multidrug resistant phenotype; and (b) characteristics of cells selected for resistance to DOX or DOX plus TFP are comparable.     

Comparison of patient self-reports and urinalysis results obtained under naturalistic methadone treatment conditions

This study examined under naturalistic assessment conditions the validity of self-reported opiate and cocaine use among 175 veterans enrolled in methadone treatment, and factors related to self-report validity, such as stage in treatment and drug of abuse. Veterans were interviewed by clinical staff about past 30-day drug use with the addiction severity index (ASI), and urinalysis results were obtained for the same 30-day interval assessed with the ASI. Analysis revealed that urinalysis generally produced higher rates of substance use than patient self-report, and with the exception of reported opiate use among new patients presenting for treatment, validity of patient self-reported drug use generally was poor with patients under-reporting both opiate and cocaine use. The findings are in marked contrast to those obtained in other studies in which participants are ensured confidentiality regarding their self-reports. Further, the results raise questions about the utility of self-report measures of substance use to assess patient progress or methadone program performance.     

Osteoradionecrosis of the Anterior Cranium

Osteoradionecrosis occurs in approximately 10% to 15% of patients following radiation therapy for head and neck cancer. In these patients, it is most commonly reported in sites involving the mandible, but it has also been reported in the maxilla, sphenoid, and temporal bones. The majority of these cases are related to some type of trauma such as dental extraction or intraoral biopsies. However, approximately 40% of these entities occur spontaneously and are felt to be secondary to cell kill in intermediate tissues such as bone and periosteum. Our literature review yielded no previously reported cases of osteoradionecrosis involving the anterior cranium. The following two cases present patients who experienced osteoradionecrosis of their frontal bone flaps following subcranial approaches for tumor resection. Both patients suffered from carcinomas involving the ethmoid sinuses; one tumor was a moderately well-differentiated squamous cell carcinoma, the other a mucinous adenocarcinoma. One patient's radiation therapy consisted of external beam photons; the other patient received external beam neutrons. Treatment for these patients, as well as possible causative factors regarding their osteoradionecrosis, are discussed.     

5,11-dimethyl-2,9-bis(phenylacetyl)-5,11-diazatetracyclo[6.2.2.0(2,7).0(4,9)]dodecane, a potent, novel analgesic.

5,11-Dimethyl-2,9-bis(phenylacetyl)-5,11-diazatetracyclo[6.2.2.0(2,7)90(4,9)]dodecane (2a) has been found to be a potent narcotic analgesic of unusual structure. All of the analgesic activity was attributable to the levorotatory isomer 2b which was approximately three times as potent as morphine in the rat. Removal of one N-methyl group from 2a reduced, but did not abolish, the analgesic activity. However N-allyl analogues were neither agonists nor antagonists. Replacement of one of the phenyls of 2a with a cyclohexyl group yielded an analogue with considerable activity. Structural similarities with derivatives of ethenooripavine are noted.