No abstract

Several reports have appeared on the use of combined radioimmunotherapy (RAIT) and chemotherapy. The choice of drug to use with RAIT and how to space the two treatments has not been completely addressed. Because every patient's cancer presents with a specific molecular phenotype, we hypothesized that it may be necessary to tailor therapy based on specific gene expression. We addressed how the form of expression of a single gene, the p53 tumor suppressor, would impact the choice of agents, as well as sequence and spacing of agents. p53 regulates cell cycle arrest to allow for DNA repair after therapy-induced small DNA damage or induction of apoptosis if damage is great and has been shown to affect chemo-and radiosensitivity of cancer cells. We established 3 stable p53 transfectants of the SKOV-3 p53null parental line (p53 wt , p53 143mut or p53 273mut ). p53 expression was confirmed using flow cytometry, using the DO1 pan-p53 Ab and the PAb240 anti-p53mut Ab. The colorimetric MTT assay was then used to measure dosedependent growth inhibition from single modality chemotherapy (doxorubicin, carboplatin, paclitaxel or topotecan) or radioimmunotherapy ( 90 Y-RS-7 IgG anti-EGP1). The % survival vs. log [drug] were plotted to obtain the IC 50 . We then used a matrix design in which we varied the sequence of the first and second modality of treatment and the spacing between the 2 treatments to determine the most synergistic and antagonistic combinations for the parental SKOV-3 and each of the 3 transfectants. The IC 50 for each therapeutic agent varied as a function of the form of p53 expressed. For example, of the 4 lines, the p53wt transfectant was the most resistant to topotecan and the 143mut was the most resistant to carboplatin. The 273mut was quite sensitive to both doxorubicin and paclitaxel, whereas the p53null and wt were not. For multimodal treatments, most combinations of RAIT and chemotherapy resulted in a 30 -40% growth inhibition (GI) and were either additive or moderately antagonistic. The 3 best (>60% GI) and 3 worst (<25% GI) combinations were identified and were unique to the parental p53null and to the 3 transfectants. Certain combinations showed clear synergy and others were antagonistic, with the first treatment modality blocking the growth inhibitory effects of the second treatment modality. The form of p53 expressed affects chemosensitivity and radiosensitivity and will influence optimal multimodal therapy with RAIT and chemotherapy and the dose-schedule (sequential with RAIT first or with drug first) when more than 1 agent is used.

No abstract

Platelet adhesion/aggregation (PAA) at a site of coronary artery stenosis is believed to be a process strongly modulated by local shear rates and the functional state of neighboring endothelium. One purpose of the present work, therefore, is to describe an in vitro model for the direct imaging of such PAA. Another is to apply the model to the question as to whether the use of nonionic vs. ionic contrast media (CM) in the presence of vascular endothelium contributes to PAA at the stenosis site. Toward these ends, we utilized a special flow chamber which incorporates a monolayer of endothelial cells (ECs), a step 66% flowpath constriction at a site preadsorbed with microfibrillar collagen, and arterial shear rates. By epifluorescence microscopy and digital image analysis of video recordings, PAA was found to be greater with dysfunctional ECs (pretreated with lysine acetylsalicyclate) than with normal ECs, thereby confirming a modulatory role in PAA of functionally intact ECs. When nonionic (iohexol) or ionic (ioxaglate, diatrizoate) CM was added to the flowing blood at a concentration of 20% by non-red cell volume, PAA was inhibited in the order diatrizoate > ioxaglate > iohexol > saline control. No inhibition by any CM was seen, however, when chamber prefill culture medium containing 20% by volume CM was displaced by CM-free blood, in simulation of bolus administration of CM. In terms of inhibition of PAA during percutaneous transluminal coronary angioplasty (PTCA), therefore, our model provides a conceptual basis by which one may anticipate in flowing blood no clear benefit of ionic over nonionic CM.(ABSTRACT TRUNCATED AT 250 WORDS)