Tumor Volume Doubling Time Research Articles

Growth Pattern Changes of Meningiomas: Long-term Analysis

Although tumors are generally expected to grow exponentially, it is not known whether meningiomas retain a constant growth rate or not because of the lack of long-term follow-up. We analyzed the long-term growth pattern of meningiomas. Twenty patients with a total of 31 meningiomas were radiologically followed for 4.1 to 18.3 years (median, 10.1 yr). Seven patients (including two neurofibromatosis cases) had incidental tumors. Another 13 patients with symptomatic tumors were followed after surgery. Their volumes were measured, and their time-volume curves were plotted. The growth curves of four atypical meningiomas fitted better to an exponential curve (R > 0.95). Two calcified tumors did not grow. Although the other benign tumors grew exponentially or linearly, their tumor volume doubling times in the initial phase were shorter than those in the later phase in most cases. Meningiomas without calcification tended to grow exponentially, whereas those with calcification were likely to reveal a linear growth pattern (P = 0.002, chi2 test). This was supported by the observation that in two patients, the tumor growth pattern changed from exponential to linear and from linear to no growth with progression of calcification. Three growth patterns of meningiomas were demonstrated. Atypical meningiomas grew exponentially. Conversely, benign meningiomas revealed exponential, linear, or no growth. The growth pattern of the latter may change with the appearance of calcification.

Lung Cancer Screening: Simulations of Effects of Imperfect Detection on Temporal Dynamics

To use a mathematic model to demonstrate effects of imperfect detection on temporal dynamics of radiologic lung cancer screening. Monte Carlo simulations of lung cancer screening programs were performed in subjects at high risk for developing cancer. The effects of detection probabilities, symptomatic presentation of tumors, tumor volume doubling time, and time between screenings were examined. Computed tomography (CT) and chest radiography models were used. For imperfect detection probabilities, the percentage of subjects with cancers detected with repeated screenings decreased to a steady-state value. The transition period was the period during which screenings were performed and detection rates decreased. At steady-state repeat screening, the proportion of subjects with cancers diagnosed at screening or by means of symptomatic presentation was determined by the annual probability of developing cancer and not by the sensitivity of the screening modality. The sensitivity of the screening technique did affect detected cancer size, number of interval cancers, and total number of cancers observed. CT was used to detect more total cancers over the course of the screening program and cancers with a smaller average size; moreover, fewer interval cancers were observed with CT screening than with chest radiography screening. Lung cancer screening with imperfect detection has a transition period between baseline screening and steady-state behavior of annual screenings. Advantages of CT screening include a decrease in the average cancer size at detection, a decrease in the number of observed interval cancers, and an increase in the total number of cancers observed. Steady-state behavior indicates that long-term trials of screening may not be necessary.

The C-neu mammary carcinoma in Oncomice; characterization and monitoring response to treatment with herceptin by magnetic resonance methods

To characterize spontaneously occurring c-neu/HER2 overexpressing tumours in oncomice and their response to herceptin by non-invasive magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI). Oncomice were monitored by localized 31P MRS during unperturbed growth and before and after treatment with 10 mg/kg herceptin (Hoffman La Roche) intraperitoneally for up to 21 days post-treatment. Vascular morphology and function was assessed by quantitation of tumour magnetic resonance (MR) relaxation rates R2* and R2 prior to and either during carbogen (95% O2/5% CO2) breathing or following administration of the blood-pool contrast agent NC100150 (Clariscan, Amersham Health). Immunohistochemistry showed strong membrane staining for HER2 protein overexpression. The 31P MRS showed only a significant (p<0.01) increase of phosphomonoester / total phosphate ratio over 21 days of growth. Herceptin increased the tumour volume doubling time compared to untreated tumours and significantly increased the phosphomonoester / beta-nucleoside triphosphate ratio 2 days after treatment (p=0.01). Tumours showed a highly heterogeneous yet significant (p<0.01) decrease or increase in R2* in response to carbogen or NC100150 respectively. The absence of a decline in tumour bioenergetics with growth, commonly seen in 31P MRS studies of transplanted rodent tumour models, coupled with the heterogeneous blood volume revealed by 1H MRI, suggest a metabolic and vascular phenotype similar to that found in human tumours.

Novel tumor-inhibiting metal complexes: Preclinical efficacy and toxicity of the lanthanum(III) complex [tris(1,10-phenantroline)lanthanum]trithiocyanate FFC24

3166 Background: The search for new agents with favorable activity in different types of cancer revealed the novel lanthanide complex FFC24 with 1,10-phenatroline as ligand and lanthanum as central metal. This complex was chosen among different lanthanide complexes for further development due to its high activity in-vitro with a GI50 value of 1.28 μM and an activity profile and a mode of action being different compared to classical platinum drugs. Methods: FFC24 was examined in vivo concerning toxicity by determining the acute intravenous median lethal dose (LD50) and the no-observed-adverse-effect-level in the rat and in the mouse. The in-vivo efficacy screening of FFC24 was performed in the DLD-1 colon adenocarcinoma xenograft model in nude mice using intravenous application. Results: Examination of the acute intravenous toxicity in Sprague Dawley rats at a dose level of 7.5, 15 or 17.5 mg/kg in 0.9 saline revealed a LD50 of 21.60 mg/kg for all animals and 11.46 mg/kg for females only after extrapolation. The NOAEL was determined to be 7.5 mg/kg. In the mouse (outbred albino), FFC24 was administered at doses of 10, 15 or 17 mg/kg and the LD50 was extrapolated to 62 mg/kg for females and males together and 26.6 for males alone. The NOAEL in the mouse was 10 mg/kg. The in-vivo efficacy testing in the DDL-1 xenograft model in comparison to MTX and CisPt was performed at 4, 8, or 12 mg/kg on days 0, 1, 2, 3 and 4 (qd5). The anti-tumor activity of FFC24 in terms of relative tumor volume doubling time respectively growth delay was comparable to CisPt and MTX without any signs of toxicity. Only slight differences concerning activity with respect to the administered dose of FFC24 were observed. Conclusions: With FFC24 a new, very promising non-platinum anti-tumor agent with a different profile of activity and a new mode of action has entered the preclinical development. No significant financial relationships to disclose.

Pronounced antitumor efficacy by extracellular activation of a doxorubicin-glucuronide prodrug after adenoviral vector-mediated expression of a human antibody-enzyme fusion protein.

Tumor-specific activation of the glucuronide prodrug of doxorubicin, N-[4-doxorubicin-N-carbonyl(oxymethyl)phenyl]-O-beta-glucuronyl carbamate (DOX-GA3), by beta-glucuronidase present in necrotic tumor areas might be improved after transduction of tumor cells to secrete a targeted form of beta-glucuronidase. To that end, we constructed an adenovirus vector, designated Ad/C28-GUSh, encoding human beta-glucuronidase fused to a human single-chain Fv (scFv) against the epithelial cell adhesion molecule (EpCAM), C28, and preceded by a signal sequence for secretion. Antibody specificity and enzyme activity were retained in the fusion protein secreted by tumor cells infected with Ad/C28-GUSh. Diffusion of fusion protein from transduced tumor cells within MCF-7 multicellular spheroids was visualized by immunohistochemistry. Treatment of spheroids with Ad/C28-GUSh and DOX-GA3 resulted in growth inhibition comparable to treatment with doxorubicin alone. Treatment of well-established FMa human ovarian cancer xenografts with intravenous injection of DOX-GA3 (500 mg/kg) resulted in a tumor volume-doubling time of 23.8 days compared to 8.0 days for phosphate-buffered saline (PBS)-treated mice. Intratumoral administration of Ad/C28-GUSh before DOX-GA3 enhanced the growth inhibition and increased the tumor volume-doubling time to 43.1 days (p < 0.01), while virus alone had no effect. Thus, we have successfully shown that an adenovirus vector encoding a secreted, targeted form of human beta-glucuronidase can further improve DOX-GA3 monotherapy.

Pathologic characterization of prostate cancers with a very low serum prostate specific antigen (0–2 ng/mL) incidental to cystoprostatectomy: is PSA a useful indicator of clinical significance?

Cystoprostatectomy specimens removed for bladder malignancy (1988–2000) at two referral centers (Mayo Clinic, Rochester, MN, The University Hospital of Innsbruck, Innsbruck, Austria) were examined for the coincidental finding of prostate cancer (PCA). Centralized examination of the prostate by a single uropathologist was performed if at the time of surgery the patient’s serum PSA was ≤2.0 ng/mL and there were no suspicious lesions by digital prostate examination. Pathologic grade, stage, morphometric volume, number of tumor foci and association with areas of high grade prostatic intraepithelial neoplasia (HGPIN) were assessed by light microscopy. DNA ploidy and cellular proliferative index were assessed through digital image analysis. Clinically significant cancers were defined as tumors with ≥0.5 cc volume, Gleason 4 or 5 architecture, pT3, positive surgical margin, multifocality >3, nondiploid DNA content or proliferation index >5%. From nearly 1600 cystoprostatectomy specimens, 129 met the enrollment criteria. Thirty-patients (23%) within this group had PCA identified. Sixty percent of these tumors met the criteria for a clinically significant cancer. Nondiploid nuclear content was present in 17%. HGPIN was present in 70% and directly abutting carcinoma in 86% of prostates. The biologic activity of PCA appears to be independent of serum PSA. Any future definition of a clinically significant PCA should not be solely based upon histologic criteria, but needs to encompass clinical parameters (age, co-morbidities) and a noninvasive assessment of tumor volume and biologic doubling time.

Modified radiosensitivity of pancreatic cancer xenografts by farnesyl protein transferase inhibitor and MEK inhibitor

We investigated the effects of the farnesyl transferase inhibitor (FTI) manumycin and the MEK inhibitor PD98059 on growth of human pancreatic cancer, with mutant (SUIT2) or wild-type (BxPC-3) K-ras, xenografted into nude mice. Tumor growth was not reduced by either of the agents at a dose of 3 mg/kg without irradiation. Growth of SUIT2 irradiated at 15 Gy or 30 Gy was reduced by manumycin and PD98059: at 15 Gy, tumor volume doubling time (TVDT) increased from 18.6+/-3.8 to 36.3+/-14.2 days with PD98059 (p<0.05); at 30 Gy, TVDT increased from 32.8+/-6.8 to 70.5+/-10.5 days and 70.7+/-1.5 days, respectively. Manumycin tended to reduce growth of BxPC-3, but the difference in TVDT was not statistically significant. PD98059 significantly increased the TVDT of BxPC-3 at 30 Gy from 34.4+/-18 to 62.6+/-9.8 at 30 Gy. The present results suggest that Ras signaling pathways are potential targets for manipulation of radiosensitivity, and that induction of an alternative pathway may enhance radiosensitivity of pancreatic cancer.

Selection of genetically distinct, rapidly proliferating clones does not contribute to repopulation during fractionated irradiation in FaDu squamous cell carcinoma.

Acceleration of clonogen repopulation during fractionated irradiation after about 3 weeks has been demonstrated previously in FaDu human squamous cell carcinoma in nude mice (Petersen et al., Int. J. Radiat. Oncol. Biol. Phys. 51, 483-493, 2001). Selection of genetically distinct, rapidly proliferating clones might contribute to this phenomenon. To address this question, three sublines (R1-R3) were established from FaDu tumors that recurred locally after fractionated irradiation. The tumors were retransplanted and irradiated under clamp hypoxia with single doses or with 18 x 3 Gy within 18 days or 36 days, followed by graded top-up doses. The results were compared with data obtained after the same treatment schedules in the parental tumor line. Histologies, tumor volume doubling times, and potential doubling times of FaDu sublines R1-R3 were not different from those of the parental line. The radiation dose required to control 50% of the tumors (TCD(50)) after single-dose irradiation of 37-38 Gy was the same for the FaDu sublines R1-R3 and the parental tumor. The top-up TCD(50) values for the FaDu sublines R1-R3 after 18 fractions within 36 days were 14-17 Gy higher than those after 18 fractions within 18 days, indicating significant repopulation. The magnitude of this effect was not significantly different between the sublines R1-R3 or between these sublines and the parental FaDu tumors. The results indicate that selection of genetically distinct, rapidly proliferating clones does not contribute to the acceleration of repopulation during fractionated irradiation in poorly differentiated FaDu tumors.

Effect of sequencing of androgen deprivation and radiotherapy on prostate cancer growth

Purpose Androgen deprivation (AD) is frequently combined with radiotherapy (RT); however, the optimal sequence in vivo is currently unknown. Previous published work from our laboratory demonstrated that AD with RT was consistent with at least an additive, and possibly supra-additive, effect with the combined approach. We, therefore, performed additional experiments to elucidate the optimal sequence. Methods and materials R3327-G Dunning rat prostate tumor cells were grown s.c. in the flanks of Copenhagen rats. Treatment was initiated when the tumor reached approximately 1 cm 3. Temporary AD was performed by a transscrotal orchiectomy followed 14 days later with androgen restoration using s.c. testosterone implants. RT was delivered using 60Co to 7 Gy. Seven groups, including the controls, were analyzed: Group 1, sham control (Day 0: AD + testosterone); 2, AD control (Day 0: AD, Day 14: testosterone); 3, RT alone on Day 7 (Day 0: AD + testosterone, Day 7 RT); 4, RT alone on Day 3 (Day 0: AD + testosterone, Day 3: RT); 5, RT during AD (Day 0: AD, Day 7: RT, Day 14: testosterone); 6, RT before AD (Day 0: RT, Day 3: AD, Day 17: testosterone); and Group 7, RT after AD (Day 0: AD, Day 14: testosterone, Day 17: RT). The doubling times for tumor growth were calculated for the seven groups from the end of treatment plus 1 day. Differences in doubling time were assessed using analysis of variance, with pair-wise comparisons accomplished using post-hoc Bonferroni tests. Results An analysis of the differences in the tumor volume doubling time as measured from the end of treatment suggests that Groups 1 and 7 were statistically different from the other groups ( p = 0.02). As expected, the sham control group had the shortest doubling time at 5.4 days and Group 7 (14 days of AD administered before RT) had the longest doubling time at 32.6 days. The findings were similar even after excluding an outlying doubling time of 85 days from Group 7 ( p < 0.0001). To assess the effect of sequencing further, only Groups 5 through 7 (excluding the outlier) were compared in an analysis of variance with post-hoc Bonferroni tests. Group 7 (RT after AD) demonstrated a significantly longer doubling time than Groups 5 and 6 ( p = 0.0024). Conclusion The results suggest that neoadjuvant AD may result in prolonged suppression of tumor growth, even after testosterone replacement.

The natural history of incidental meningiomas.

Little information about the natural history of incidental meningiomas exists in the literature. The aim of this study was to determine the natural history of asymptomatic meningiomas by comparing different methods of growth rate calculation to establish a strategy for dealing with these tumors. In 47 asymptomatic patients, hospital charts, follow-up records, and imaging studies were reviewed. Of these patients, 6 underwent surgery. Tumor growth rates were determined by calculating the absolute and relative growth rates and the tumor volume doubling times. In 41 patients with conservative management, the average tumor size was 9 cm(3), and the majority (66%) of growth rates were less than 1 cm(3)/yr. The absolute growth rate ranged from 0.03 to 2.62 cm(3)/yr (mean, 0.796 cm(3)/yr). Relative annual growth rates ranged from 0.48 to 72.8% (mean, 14.6%). The tumor doubling time ranged from 1.27 to 143.5 years (mean, 21.6 yr). A moderate correlation between the age and growth rates was found. In young patients, annual growth rates tended to be higher and tumor doubling times shorter. There was no clear correlation between the initial tumor size and tumor doubling time. The mean annual growth rate of meningiomas with calcification was lower than in tumors without calcification. Also, tumors with hypointense or isointense T2 signals on magnetic resonance imaging had a lower growth rate. In the group of six patients with surgical excision, tumor growth rates were higher and tumor doubling times shorter than in the nonsurgical group. The majority of incidental meningiomas show minimal growth; thus, they may be observed without surgical intervention unless specific symptoms appear. Tumor growth is associated with patient age. The initial tumor size is not considered a predictive factor for tumor growth. Radiological features, such as calcification or T2 signal intensity, may provide useful information to predict the growth potential of meningiomas.

Establishment and characterization of human uveal malignant melanoma xenografts in nude mice.

The purpose of this study was to develop a suitable animal model for the investigation of the pathogenesis and therapy of uveal malignant melanoma. Eight choroidal malignant melanomas from eight patients were transplanted into nude mice in an attempt to establish a serially transplantable tumour model. Tumour tissue blocks (2 x 2 x 2 mm) from enucleated eyes with choroidal malignant melanoma were transplanted subcutaneously into the flanks of nude mice. The growing tumours were measured and serially transplanted. The tumour samples were investigated by histology, immunohistochemistry and electron microscopy. Only one of the eight transplanted primary tumours (13%) was established as a xenograft in nude mice. Furthermore, the take rate of the transplantable tumour was low (13%). The growth of the tumour fitted a Gompertz function, and the calculated tumour volume doubling time was 54 days. The transplanted tumour cells were epithelioid and slightly larger than the primary tumour cells and had prominent nucleoli. However, the transplanted tumour retained a morphological appearance similar to that of the primary tumour. Immunohistochemical examinations demonstrated that the cells preserved the characteristic properties of malignant melanoma. However, the transplanted cells demonstrated vimentin reactivity, whereas the primary tumour cells were negative for vimentin. It can be concluded that a new experimental model of malignant uveal melanoma with tumours that were easy to observe and access was established in nude mice.

Is clinical growth index a reliable predictor of tumour growth in vestibular schwannomas?

We have assessed the clinical growth index as an indicator of tumour growth rate in 50 patients with a vestibular schwannoma. Clinical growth index was calculated by measuring the length of history and dividing it by the maximum tumour diameter. Total tumour volumes were also measured from all MRI examinations and an effective tumour volume doubling time was calculated. Radiological growth measurements demonstrated involution in 10/50 patients. The median volume doubling time was 1.65 years (range 20.9-46.3 months, skewness 1.72 years). The median clinical growth index was 0.030 cm per month (range 0-0.270 cm per month, skewness 2.398). There was no significant correlation between volume doubling time and clinical growth index. Identification of rapidly growing tumours with clinical growth index >0.025 cm/month had a positive predictive value of 61%, negative predictive value of 48%, false-positive rate of 30% and false-negative rate of 52%. In conclusion, we have shown that the growth rate of vestibular schwannoma is not related to the clinical growth index and we recommend that this measure should be abandoned in the clinical management of patients where conservative management regimes are being considered.

Synthesis, and in vitro and in vivo evaluation of a diphenylchlorin sensitizer for photodynamic therapy

This paper reports the synthesis of a new diphenylchlorin photosensitizer, 2,3-dihydro-5,15-di(3,5-dihydroxyphenyl)porphyrin (SIM01). The photodynamic properties, cell uptake and localization of SIM01 were compared with those of structurally related meso-tetra(hydroxyphenyl)chlorin (m-THPC). In vitro studies were conducted on rat glioma cells (C6) and human adenocarcinoma (HT-29), and in vivo studies on human colon adenocarcinoma cells (HT-29) and human prostate adenocarcinoma cells (PC3). Both dyes showed an absorption maximum at around 650 nm, with a molar extinction coefficient of 13 017 M −1 cm −1 for SIM01 and 22 718 M −1 cm −1 for m-THPC. Their capacity to generate singlet oxygen was identical, but differences in partition coefficients indicated that SIM01 was slightly more hydrophilic. In vitro, SIM01 was slightly more phototoxic than m-THPC for C6 cells (4.8 vs. 6.8 μg ml −1). However, phototoxicities were nearly identical for HT29 cells (0.45 μg ml −1 for 5 h incubation followed by 300 mW, 20 J cm −2). Pharmacokinetics in vivo in mice, as determined by fibre spectrofluorimetry, showed that the SIM01 fluorescence signal in the tumor was maximal between 6 and 12 h after injection, as compared to 72 h for m-THPC. With a 2 mg kg −1 dye dose and laser irradiation at 300 J cm −2 (650 nm, 300 mW), the optimal PDT response occurred when the interval between injection and irradiation was 6 h for SIM01 and 24 h for m-THPC. For SIM01 with 5 mg kg −1 injection, the optimal PDT response occurred with a 12 h delay and with the same irradiation parameters as described above, in this case the tumor response showing 40% growth. Considering the tumor volume doubling time, the value was 6.5 days in the control group and increased to 13.5 days with SIM01. Thus, SIM01 may be a powerful sensitizer characterized by strong in vitro and in vivo phototoxicity and faster tissue uptake and elimination than m-THPC.

Growth pattern and rate in residual nonfunctioning pituitary adenomas: correlations among tumor volume doubling time, patient age, and MIB-1 index.

Surgical cure can be achieved in pituitary adenomas when they are completely removed. It is controversial whether postoperative radiation therapy should be given to prevent recurrence, and whether an early reoperation should be performed for residual adenomas, because we have little information about the natural history of postoperative residual adenomas. The residual tumor volume was serially measured in 40 nonfunctioning pituitary adenomas (NFPAs) and the tumor volume doubling time (TVDT) was calculated. Correlations between the patients' age, tumor volume, log TVDT, and MIB-1 index were examined. Other factors including the patient's sex, cavernous sinus (CS) invasion by the tumor, or presence of an intratumoral cyst were analyzed to assess their influence on the TVDT. Values are expressed as the means +/- standard deviations. Thirty-eight adenomas increased in volume and two decreased during a follow-up period ranging from 4 to 141 months (mean 52.5 months). Exponentially linear tumor growth was observed in the 38 growing adenomas regardless of the residual tumor volume, with the TVDT ranging from 506 to 5378 days (mean 1836 days). The patients' age was 57.1 +/- 15.7 years (range 15-79 years), the tumor volume at the beginning of the magnetic resonance imaging observation period was 2.5 +/- 2.2 cm3 (range 0.07-14.5 cm3), and the MIB-1 index was 0.73 +/- 0.68% (range 0.1-2.9%). There was a correlation between the log TVDT and patient age (R = 0.73), an inverse correlation between the log TVDT and MIB-1 index (r = -0.49), and an inverse correlation between the MIB-1 index and patient age (r = -0.61). A significant difference (p = 0.0001) was noted between the TVDT (1,106 days) in the 19 patients younger than 61 years of age and the TVDT (2566 days) in the 19 patients who were 61 years of age or older. There was also a significant difference (p = 0.0002) between the age (50.8 +/- 15.3 years) of the patients with rapidly growing tumors (TVDT < 1,836 days, 24 patients) and the age (69.1 +/- 7.6 years) of the patients with slowly growing tumors (TVDT> 1836 days, 14 patients). Other factors including the patients' sex, CS invasion, and intratumoral cyst formation did not affect the TVDT of residual NFPAs. The tumor growth rate of residual NFPAs is strongly influenced by the patient's age. The TVDT in elderly patients is much longer than that previously reported. Treatment strategies that take into consideration the natural history of residual adenomas should be established especially in the elderly population.

Fast-growing squamous cell lung cancer

We here report a case of squamous cell carcinoma of the lung, with an unusually fast tumor growth rate, so fast that its early detection was impossible even with two sequential chest roentgenograms taken only 36 days apart. Literature related to the concept of cell growth kinetics was reviewed, and the tumor volume doubling time that characterizes any measurable tumor was calculated for our case accordingly, based on the single lesion found on the plain chest film, with the best possible estimation of its volume. We concluded that, to the best of our knowledge, a squamous cell carcinoma of the lung that grew so fast (with a tumor doubling time less than 7.5 days) has not yet been reported to date; neither has a bronchogenic carcinoma of any cell type been reported with such a presentation. Given that a patient aged 81 belonged to a group usually with slower growth in tumor cell kinetics, the behavior of his tumor was indeed uncommon.

Function of the Exon 7 Deletion Variant Estrogen Receptor α Protein in an Estradiol-Resistant, Tamoxifen-Sensitive Human Endometrial Adenocarcinoma Grown in Nude Mice

Background. In addition to hormone and DNA binding, interactions, including competition with other proteins, appear to be a critical component of transcriptional regulation by the estrogen receptor alpha (ERα). In vitro studies suggest that exon deletion (Δ exon) variant forms of ERα may also play an important role in determining the progression from hormone dependence to hormone independence in receptor positive tumors.Methods. We investigated the presence of ERα mRNA and protein variants and their possible role in a moderately differentiated human endometrial adenocarcinoma grown in nude mice. In addition to wild-type (wt), RT-PCR assay of the tumor revealed the presence of two mRNA variants, a low concentration of Δ5 and a high concentration of Δ7 ERα. We detected wt, Δ7, and Δ5,7 mRNA by sequencing the transcripts after stable transfection of three HeLa cells with either splice variant. The linked in vitro translation/transcription assay of the transfected cells and the Western blot analysis of the original tumor generated both wt (66 kDa) and Δ7 (52 kDa), Δ5,7 (46 kDa) ERα proteins.Results. Tumor growth was characterized as estradiol and progesterone resistant but tamoxifen sensitive, i.e., neither estradiol nor progesterone treatment altered the growth rate, whereas tamoxifen treatment significantly increased the tumor volume doubling time. Estradiol treatment decreased the wt and increased the Δ7 variant ERα protein expression significantly in a dose-dependent manner. Tamoxifen treatment, however, increased the expression of both proteins whereas progesterone had no effect. Estradiol treatment did not influence expression of the Δ5,7 variant protein, which increased significantly in the tamoxifen-treated tumors. Gel mobility shift assays revealed that both wt and Δ7 ERα proteins bind to the consensus DNA sequence, whereas the Δ5,7 variant protein did not.Conclusions. We conclude that estradiol, tamoxifen, and progesterone regulate wt and variant ERα mRNA and protein expression separately and differently and that this hormonal regulation probably occurs, via different mechanisms, at the transcriptional or posttranscriptional level. The Δ7 variant ERα may play a crucial role in the determination of hormone sensitivity and thus in the outcome of hormone treatment of human endometrial adenocarcinomas.

Effective treatment of experimental DU-145 prostate cancers with targeted cytotoxic somatostatin analog AN-238

We evaluated the effectiveness of targeted cytotoxic analog of somatostatin (SST) AN-238, consisting of 2-pyrrolinodoxorubicin (AN-201) linked covalently to SST octapeptide carrier RC-121 in DU-145 human androgen-independent prostate cancers xenografted into nude mice. We also investigated the expression of mRNAs for SST receptor subtypes 2A and 5 (sst2A and sst5) in DU-145 tumors. After 8 weeks of treatment, AN-238 practically arrested the proliferation of DU-145 cancers. The tumor volume in nude mice that received 4 injections of AN-238 at the dose of 150 nmol/kg was 63.4+/-6.7 mm3, nearly 4 times smaller than that in controls which measured 249.1+/-36.3 mm3 (p<0.001). Treatment with AN-238 lowered tumor weight by 68% (p<0.01) compared with the control group and extended the tumor volume doubling time to 184.1+/-69.4 days, versus 32.1+/-6.6 days in controls (p<0.05). No toxicity-related deaths occurred during treatment with AN-238. Cytotoxic radical AN-201 administered alone or in an unconjugated mixture with carrier RC-121 inhibited the growth of DU-145 tumors only after the third and fourth injection and was toxic. The expression of mRNA for sst2A and sst5 was detected in all specimens of control DU-145 tumors and in tumors treated with AN-238. The present study demonstrates the high efficacy of SST-receptor-targeted chemotherapy in a model of human androgen-independent prostatic carcinoma.

Intratumoral Administration of Paclitaxel in an In Situ Gelling Poloxamer 407 Formulation

In order to examine the efficacy of paclitaxel (Taxol®, Bristol-Myers Squibb) after administration locally at the tumor site, we have developed a thermo-reversible gelling formulation in poloxamer 407 (Pluronic® F-127) solution. Paclitaxel was incorporated in poloxamer 407 [20% (w/w)] at 0.5- and 1.0-mg/mL concentrations. The in vitro release studies were carried out in phosphate-buffered saline (pH 7.4) at 37°C. Control and paclitaxel–poloxamer 407 formulations were administered intratumorally at a dose of 20 mg/kg in B16F1 melanoma-bearing mice. The change in tumor volume as a function of time and the survival of treated animals were used as measures of efficacy. Poloxamer 407 solution undergoes a reversible sol–gel transition when the temperature is raised to above 21°C. In vitro paclitaxel release from poloxamer 407 gels was very slow (only 6.1% after 6 hr) probably due to the poor aqueous solubility of the drug. Significant enhancement in the anti-tumor efficacy was noted following intratumoral administration of paclitaxel–poloxamer 407 formulation. The initial tumor growth rate was delayed by 67% and the tumor volume doubling time was increased by 72% relative to saline control. In addition, more than 91% of the tumor-bearing animals that received paclitaxel in poloxamer 407 gel survived on day 15 post-administration as compared to 58% in the control group. The results of this study show significant benefit of paclitaxel for solid tumor when administered locally in an in situ gelling poloxamer 407 formulation.

Antitumor effect of VNP20009, an attenuated Salmonella, in murine tumor models.

VNP20009, a genetically modified strain of Salmonella typhimurium with deletions in the msbB and purI loci, exhibited antitumor activities when given systemically to tumor-bearing mice. VNP20009 inhibited the growth of subcutaneously implanted B16F10 murine melanoma, and the human tumor xenografts Lox, DLD-1, A549, WiDr, HTB177, and MDA-MB-231. A single intravenous injection of VNP20009, at doses ranging from 1 x 10(4) to 3 x 10(6) cfu/mouse, produced tumor growth inhibitions of 57-95%. Tumor volume doubling time, another indicator for tumor growth inhibition, also significantly increased in mice treated with VNP20009. Using mice with immune system deficiencies, we also demonstrated that the antitumor effects of VNP20009 did not depend on the presence of T and B cells. In addition, VNP20009, given intravenously, inhibited the growth of lung metastases in mice. Only live bacteria showed the antitumor effect.

Analysis of hepatocellular carcinoma tumor growth detected in sustained responders to interferon in patients with chronic hepatitis C1

By analyzing a tumor growth of hepatocellular carcinoma (HCC) detected in sustained responders (SR) to interferon (IFN) therapy for chronic hepatitis C, we sought to determine the duration of follow up in SR that would be sufficient to detect HCC. In addition, we sought to elucidate the presence of HCC, which truly developed after the eradication of hepatitis C virus (de novo HCC development). Tumor volume doubling time (DT) was calculated in a total of 46 cases of HCC detected in SR after IFN therapy. Based on DT, the annual growth rate was estimated for each tumor. Survival was compared between patients with HCC < or = 30 mm and patients with HCC > 30 mm in diameter. Doubling time in SR was similar to the previously reported DT of HCC irrespective of IFN therapy. However, extensive DT was observed in three HCCs despite relatively poor differentiation, which may represent de novo HCC development. In the analysis of tumor growth, all HCCs grew to exceed 20 mm in estimated diameter between 6 months and 7 years after the end of IFN therapy. Better survival was observed in patients with HCC < or = 30 mm in diameter compared with patients with HCC > 30 mm (P = 0.0107). In surviving patients, recurrences of HCC were very infrequent. We may be able to detect most HCC in SR between 6 months and 7 years after IFN therapy. However, we cannot neglect the presence of de novo HCC development after the eradication of HCV, which makes it difficult to determine completely sufficient follow-up duration after IFN therapy in this population.