Radiobiological studies of PC-3 and DU-145 human prostate cancer cells: x-ray sensitivity in vitro and hypoxic fractions of xenografted tumors in vivo.

PURPOSE: To determine the quantitative responses to x-irradiation of exponentially growing human prostatic cancer cell lines PC-3 and DU-145 in vitro, and to determine the hypoxic percentages of these two cell lines when grown in vivo as xenografted solid tumors in nude mice. METHODS AND MATERIALS: Radiation survival in vitro was quantitated using both single-hit, multitarget and linear-quadratic formalisms. Hypoxic fractions in vivo were determined from tumors of average sizes of about 750 mm3 using clonogenic excision assay. RESULTS: In vitro, the average single-hit, multitarget survival values for 7 replicate experiments for the DU-145 line were n = 1.92 (1.39-2.65), Dq(Gy) = 1.25, and Do(Gy) = 1.91 (1.88-1.94) (all values in parentheses indicate 95% confidence limits). For the PC-3 line (10 replicate experiments), these values were n = 2.84 (2.11-2.79), Dq(Gy) = 1.02, and Do(Gy) = 1.06 (0.87-1.25). For the linear-quadratic formalism, values of alpha(Gy-1 x 10(1) and beta(Gy-2 x 10(2) for the DU-145 and PC-3 lines were, respectively, 1.55 (0.42) and 5.21 (1.09); and 4.87 (1.11) and 5.50 (1.88). The mean percentage survival of the DU-145 and PC-3 lines at a dose of 2 Gy were, respectively, 59.8 (53.3-67.0) and 32.0 (25.8-38.2). In vivo, the hypoxic fractions for the DU-145 and PC-3 tumors were, respectively, 7.20 (4.30-11.5), and 52.3 (42.8-63.9). RESULTS: The data from the in vitro experiments show that the DU-145 cell line is significantly more radioresistant than the PC-3 cell line. In vivo, the DU-145 tumors exhibit a significantly lower hypoxic percentage than do PC-3 neoplasms. CONCLUSIONS: Results indicate that significantly variability exists within human prostate tumors in regard to both intrinsic radiosensitivity in vitro and levels of hypoxia in vivo. Because these data appear to be the first published information on the intrinsic radiosensitivity and intratumor hypoxia characteristics of human prostate cancer, additional studies are needed to define the distributional aspects of these clinically relevant endpoints.

Modification of the volumetric growth responses and steady-state hypoxic fractions of xenografted DLD-2 human colon carcinomas by administration of basic fibroblast growth factor or suramin.

We studied the growth characteristics and hypoxic fractions of DLD-2 human colon tumours xenografted into male nude mice either in the unperturbed state or after i.p. injection (q.i.d. x 7) of basic fibroblast growth factor (0.25 mg kg-1) or suramin (50 mg kg-1). Hypoxic fractions were measured by clonogenic excision assay 1 day after administration b FGF or suramin was stopped. As compared to controls, the growth of tumours in b FGF treated mice was increased by a factor of 1.5 as indicated by the relative volumes of tumours on the day of excision. Similarly, suramin decreased the growth of DLD-2 tumours by a factor of 1.6. The percentage of hypoxic cells in control neoplasms was 42.9% (95% confidence limits 34.2-52.1%). In mice that received basic fibroblast growth factor injections, hypoxic fractions decreased to 19.1% (95% confidence limits 13.5-26.9%). In contrast, in mice treated with suramin, the percentage of hypoxic cells increased to 74.0% (95% confidence limits 65.3-83.9%). These data indicate that the biology of solid tumours can be significantly modified by alteration of growth factor status.

Effect of preirradiation of transplantation site on growth characteristics and hypoxic fractions in human colon tumor xenografts.

The volumetric growth curves and hypoxic fractions of seven different human colon tumor lines (clone A, clone D, WiDR, SW480, SW620, DLD-2, and HCT-8) xenografted into the flank regions of either unirradiated nude mice or mice that had received 17.5 Gy of 250-kVp X-rays 1 day prior to implantation were biomathematically analyzed using the Verhulstian equation. Significant variation was found among tumors with respect to both initial growth rates (r, days-1) and theoretical final volumes (carrying capacities, K, mm3). In radiation-damaged normal tissue, tumors grew relatively well for about the first 2 wk postimplantation, attaining volumes of about 70 to 155 mm3. Then, tumor growth rates altered. This effect varied from relatively minor effects on growth rate (tumors of clones A and D) to inhibition of growth, with actual decreases in tumor volume (e.g., WiDr, SW480, SW620, HCT-8, and DLD-2). After this short-term transience in growth kinetics, neoplasms began to steadily regrow at about 3 wk postimplantation, albeit at a slower rate than that seen in controls. Tumor bed effect values were calculated using the ratio of times at which control tumors and tumors growing in the radiation-injured tissue reached a volume of 7.5% of the K values derived from the respective control growth curves. Values for clone D, clone A, and WiDR, SW480, SW620, DLD-2, and HCT-8 tumors were, respectively, 1.89, 2.41, 3.48, 3.62, 2.82, 3.66, and 3.65, indicating that tumor bed effect responses varied by almost 100%, even for cancers of the same neoplastic class. Also, the hypoxic fractions of all tumors growing in radiation-damaged sites were increased as compared with levels in controls.