Purpose-The goal was to determine if prostate tumor cells containing a mutant α6 integrin would be defective in tumor re-population following clinically relevant fractionated ionizing radiation (IR) treatments.Material and methods-Human prostate cancer cells derived from PC3N cells were used which conditionally expressed a cleavable, wild type form of α6 integrin (PC3N-α6-WT) or a mutated noncleavable form of α6 integrin (PC3N-α6-RR). The resulting tumor growth before, during and after fractionated doses of IR (3 Gy × 10 days) was analyzed using the endpoints of tumor growth inhibition (T/C), tumor growth delay (T-C), tumor doubling time (Td) and tumor cell kill (Log 10 cell kill).Results-The T/C values were 36.1% and 39.5%, the T-C values were 20.5 days and 28.5 days and the Td values were 5.5 and 10.5 days for the irradiated PC3N-α6-WT and PC3N-α6-RR cells, respectively. The Log 10 was 1.1 for the PC3N-α6-WT cells and 0.8 for the PC3N-α6-RR cells. The tumor response to IR was altered in tumors expressing the mutant α6 integrin as indicated by a significant increase in tumor growth inhibition, an increase in tumor growth delay, an increase in tumor doubling time and an increase in tumor cell kill.Conclusions-Blocking integrin cleavage in vivo may be efficacious for increasing the IR responsiveness of slow growing, pro-metastatic human prostate cancer.

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BackgroundChordoma is a rare invasive bone tumor that may occur anywhere along the neuraxis. A total of three primary histological varieties have been identified: conventional, chondroid, and dedifferentiated.Case presentationWe report a case of an 8-year-old white girl who presented with conventional chordoma, was treated with surgical resection and mixed proton and photon beam therapy, and had a recurrence in the resection cavity 2.5 years later with dedifferentiated morphology. The recurrent tumor did not express brachyury, a recently identified protein specific to tissue of notochordal origin.ConclusionsThe short time period between radiation therapy and dedifferentiation, low dose of photons, and rarity of dedifferentiated skull base chordomas in pediatric patients should alert clinicians to the possibility of chordoma dedifferentiation after proton beam therapy.

Active folic acid degradation with the formation of pterin-6aldehyde is a previously undescribed characteristic of cancer cells in tissue culture. Neither normal adult epithelial and fibroblastic cells nor human amniotic cells nor mouse embryonic fibroblasts degrade folic acid to a measurable degree.Twenty-nine patients whose diagnoses were not revealed until after the test of their first morning urine for pterin-6aldehydewas completed were studied for the presence or absence of pterin-6aldehyde by thin-layer chromatography. (3)(4)(5)(6)(7)(8).Biopterin, a guanosine and not a folate derivative, and its oxidation products (xanthopterin, isoxanthopterin, and leucopterin), are also found in human urine (9, 10). A sluggishly active folate cleavage enzyme has been demonstrated in crude liver extracts of animals (11,12), and an inert folate cleavage enzyme, activated by HCI, has been reported in human red blood cells (13). Cleavage of folic acid occurs between C-9 and N-10, immediately yielding pterin-6-aldehyde and p-aminobenzoylglutamate. When [3H]folic acid was injected into men, [3H]pteridines were found in the urine (14).Moreover, when either we or our gouty patients consumed 50-100 mg of folic acid, the next first morning's freshly voided urine, which was protected from light and oxidation, contained not only folic acid but considerable quantities of pterin-6-aldehyde, pterin-6-carboxylate, and pterin, indicating, we believe, active folate degradation in vivo.Herein, we describe the excretion and identification of pterin-6-aldehyde in the culture media of malignant cells, but its absence in the media of adult normal cells, embryonic cells, and amniotic cells. We also report the demonstration by thinlayer chromatography of pterin-6-aldehyde in the urine of patients with cancer, in concentrations greater than 300 nmol/ml, and its absence in adequately studied patients without malignancies. MATERIALS AND METHODSTissue Culture. We used McCoy's 5a (modified) medium without Bactopeptone and added 15% dialyzed fetal calf serum and gentamicin (50,ug/ml). In the reconstructed medium we varied the folic acid from 10 ag/liter to 10 mg/liter and the vitamin B12 from 0.5 ,g/liter to 2 mg/liter. In some experiments we added N5-methyltetrahydrofolate in place of folic acid. All cultures were shown to be concurrently PPLO (pleuropneumonia-like organism)-negative by culture for 3 weeks on GIBCO broth and pour plates. The cell types studied are listed in Table 1.The fluorescent substance was isolated from two sets of experiments. In the first set the cells were grown in Falcon plastic 75 cm2 flasks containing 10 ml of medium for 2-3 days, depending on the cell doubling time. The medium was discarded and replaced by fresh medium, which was allowed to remain in the flask for the ensuing 36-72 hr in order to ensure collection during logarithmic phase growth of the cells. Controls consisted of simultaneously incubated media without cells. All determinations were done in quadruplicate. In the second set each cell type was gr...

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