Absolute and relative activities of platinum-complexes on human tumors as evaluated by an antimetabolic in vitro assay

An in vitro assay, which evaluates drug effect on ³H-thymidine incorporation, was used to investigate the absolute and relative activities of cisplatin (DDP), carboplatin (CBDCA) and iproplatin (CHIP) on 317 specimens from untreated tumors, including breast and ovarian cancers and malignant melanomas. Similar activities were generally observed for DDP and CHIP, whereas CBDCA exhibited a lower, although not significantly different cytotoxicity on breast and ovarian cancers. The relative activities of Platinum analogues were analyzed on 239 two-way drug sensitivity comparisons. The overall agreement rates ranged from 80.2 to 83.9% for the different comparisons. High coresistance, from 61.1 to 93.8%, was observed for all the comparisons, regardless of the tumor type. Cosensitivity rates were poor for breast and ovarian cancers, from 0 to 37.5%, whereas for melanomas an association in sensitivity was observed in 80% of the cases.     

Cellular expression and genetic control of ABH antigens in primary sensory neurons of marmoset, baboon and man

ABH antigens have been demonstrated in the posterior root ganglia (PRG) of 3 primate species (marmoset, baboon and man). Their expression corresponded to the ABO phenotype of the individual and was independent of the secretor gene. In marmosets more cells were positive for H (33 +/- 9%) than for A (19 +/- 6%). In baboons A or B antigens were more easily detected (66 +/- 9%) than the H antigens (48 +/- 5%). In humans more than two-thirds of PRG cells were positive for H but only a small proportion of these were positive for A or B. The ABH antigens were found mainly in the small and intermediate-size neurons whose central processes project to lamina II of the spinal cord posterior horn. Unipolar neurons of the Gasserian ganglion, neurons of the mesencephalic nucleus of the trigeminal nerve and of some visceral ganglia have also been shown to express these antigens which are also present in the fibre layer and glomeruli of the olfactory bulbs.     

Reversible inhibition of spermatogenesis in rats and monkeys with a new class of indazol-carboxylic acids

The effect of oral administration of $\text{AF 1312}\text{TS}$ upon the testicular germinal epithelium was studied in the rat and monkey. A single oral dose of 100 or 200 mgm/kgm given to mature male rats was not effective, but five consecutive doses of 200 mgm/kgm produced marked decrease in testicular weight and complete inhibition of spermatogenesis, while the weight and histology of the prostate and seminal vesicles were not affected. Daily doses of 10 mgm/kgm for 37 weeks or five consecutive doses of 50 mgm/kgm for 1 week were ineffective in the monkey. However, when the five dose regimen was followed by single weekly doses of 50 mgm/kgm for 6 months, complete inhibition was achieved and maintained in the monkey after 8 weeks. Daily doses of 100 mgm/kgm for 6 months resulted in inhibition of spermatogenesis.Preliminary studies with AF 1890 (an analog of $\text{AF 1312}\text{TS}$) given at levels of 50 mgm/kgm for 5 days to rats resulted in complete inhibition of spermatogenesis. The activity of this analog was four times greater than $\text{AF 1312}\text{TS}$. In monkeys, a daily dose of 200 mgm/kgm for 2 weeks also resulted in suppression of spermatogenesis.     

Genomic allelotyping for distinction of recurrent and de novo hepatocellular carcinoma after orthotopic liver transplantation.

Distinction between recurrent and de novo hepatocellular carcinoma (HCC) after orthotopic liver transplantation (OLT) bears important clinical and therapeutic implications. Techniques for molecular profiling of clinically suspected de novo and recurrent HCC are required since the histological/clinical discrimination of donor vs. recipient tumor origin is difficult. Multiple PCR amplification of 16 highly polymorphic short tandem repeat (STR) DNA sequences (routinely used for paternity and forensic assays) was applied in two patients who developed a second HCC after OLT. In both patients the technique provided reliable evidence that the two second HCC were recurrences of the primary tumor. Multiple STR genetic allelotyping is an effective tool for clear-cut discrimination of donor/recipient origin of a second HCC after OLT. Its application could be of great therapeutic relevance for such OLT patients.     

Modulation by lonidamine on the combined activity of cisplatin and epidoxorubicin in human breast cancer cells

The ability of lonidamine (LND), an energolytic derivativeof indazole-carboxylic acid, to modulate the cytotoxic activityof cisplatin (CDDP) and epidoxorubicin (EPI), singly orin combination, was investigated in two human breastcancer cell lines (MCF7 and T47D). A 72-hrpost-incubation with a non-cytotoxic concentration of LND (75M) increased the activity of a 1-hr CDDPtreatment as well as that of a 1to 16-hr EPI treatment. A different pattern ofinteraction among the drugs and modulator was observedas a function of the sequence of drugtreatment. Specifically, supra-additive or additive effects of thecombination were obtained in the two cell linesaccording to the different treatment schemes. In particular,the maximum potentiation was observed in MCF7 cellssimultaneously exposed to CDDP, EPI and LND for1 hr and then post-incubated with LND for72 hr, and in T47 first exposed toEPI and LND, then to CDDP and LND,and finally post-incubated with LND. Flow cytometric analysisof MCF7 cell distribution in the different cyclephases showed that combined treatment with EPI/CDDP/LND wasable to stabilize cell cycle perturbations (mainly G₂Maccumulation) induced by individual agents. The ability ofLND to potentiate CDDP and EPI cytotoxicity, andthe consideration that LND causes side effects differentfrom those caused by alkylating agents and anthracyclines,make this compound an attractive candidate for multidrugcombination therapy in breast cancer.     

Schedule-dependent modulation of idarubicin cytotoxicity by lonidamine in human lymphoma cell lines

The ability of lonidamine (LND), an energolytic derivative of indazol-carboxylic acid, to modulate the cytotoxic activity of idarubicin (IDA) and doxorubicin (DX) was investigated in two human lymphoma cell lines (H9 and U937). A different pattern of interaction between the drugs was observed as a function of treatment sequence. Specifically, a 24-h postincubation with a non-cytotoxic concentration of LND (75 mu M) increased the activity of a 1-h anthracycline treatment in both cell lines. However, the extent of potentiation for IDA was more than twofold that of DX. No enhancement of anthracycline activity was observed when LND preceded IDA. For comparative purposes, the modulating effect of all-trans-retinoic acid (ATRA) on the cytotoxicity of IDA was evaluated according to different treatment schemes in both lymphoma cell lines. In U937 cells, which undergo monocytic differentiation after exposure to retinoids, a marked increase in LDA activity was obtained following a 48-h postincubation with 1.5 mu M ATRA. No potentiation of anthracycline activity was obtained using the opposite drug sequence. In H9 cells, no significant interference between ATRA and IDA was observed independent of the modality of drug administration. The ability of LND to potentiate IDA activity, and the consideration that LND causes side effects different from those caused by anthracyclines, make this compound an attractive candidate for multidrug combination therapy in hematological neoplasms.     

Emotion-related cerebral asymmetry: hemodynamics measured by functional ultrasound

This study assessed the use of transcranial Doppler ultrasound in detecting selective changes in cerebral blood flow velocity during emotional processes. The role of the respective hemispheres in emotional processing is controversial. Cerebral control of emotional processing has previously been investigated by analysis of patients with unilateral brain damage, experiments with selective stimulation of only one hemisphere, and more recently by imaging techniques measuring local cerebral blood flow. We investigated mean flow velocity continuously and simultaneously in both the right and left middle cerebral arteries (MCAs) in 16 healthy right-handed young subjects at rest and during the performance of three tasks: task 1: 15 slides with nonemotional content; task 2: 15 slides with negative emotional content; task 3: 15 slides with nonemotional content with different content from that in task 1. The three tasks produced significantly different effects on the right and left hemispheres. During the two nonemotional tasks the increase in mean flow velocity over basal values was similar in the two MCAs (task 1: left MCA = 3.27 ± 1.9%; right MCA = 3.63 ± 2.1%; task 3: left MCA = 2.42 ± 0.7%; right MCA = 2.56 ± 1.3%); the negative emotional task was accompanied by a significantly higher increase in the right (11.31 ± 1.6%) than in the left MCA (4.72 ± 3.7%; analysis of variance two-way interaction: side of recording x task, F = 43.6, P < 0.001). These results show the possibility of obtaining specific functional information from bilateral transcranial Doppler ultrasound and suggest the involvement of the right hemisphere in emotional processing. Received: 4 March 1999 Received in revised form: 29 June 1999 Accepted: 5 August 1999     

Stabilization of rat serum proteins following oral administration of fish oil

The mechanism of action of fish oil (FO), currently used in different chronic inflammatory conditions such as rheumatoid arthritis (RA), is not completely understood, although it is thought that it could alter the metabolism of endogenous autacoids. In addition, we hypothesized that the known capability of fatty acids (FA) of stabilizing serum albumin and perhaps other proteins, may be of pharmacological relevance considering that it is shared by other anti-rheumatic agents (e.g. nonsteroidal antiinflammatory drugs). Thus, we studied the effect of oral administration of FO and corn oil (CO), a vegetable oil with a different composition, on the stability of rat serum proteins, evaluated by a classical in vitro method based on heat-induced protein denaturation. FO, and, to a lower extent, CO inhibited heat-induced denaturation of rat serum (RS): based on the inhibitory activity (EC50) of the major fatty acids against heat-induced denaturation of RS in vitro, it was possible to speculate that in vivo effects of palmitic acid (C16:0) and eicosapentaenoic acid (EPA, C20:5, n-3) may be more relevant than that of linolenic acid (C18:2). To better investigate this phenomenon, we extracted albumin from the serum of animals treated or not with FO with a one-step affinity chromatography technique, obtaining high purity rat serum albumin preparations (RSA-CTRL and RSA-FO), as judged by SDS-PAGE with Coomassie blue staining. When these RSA preparations were heated at 70 degrees C for 30 min, it was noted that RSA-FO was much more stable than RSA-CTRL, presumably due to higher number of long chain fatty acids (FA) such as palmitic acid or EPA. In conclusion, we provided evidences that oral administration of FO in the rat stabilizes serum albumin, due to an increase in the number of protein bound long chain fatty acids (e.g. palmitic acid and EPA). We speculate that the stabilization of serum albumin and perhaps other proteins could prevent changes of antigenicity due to protein denaturation and glycosylation, which may trigger pathological autoimmune responses, suggesting that this action may be involved in the mode of action of FO in RA and other chronic inflammatory diseases.