Based on the observation that removal of tumors from metastatic organs reversed their chemoresistance, we hypothesized that chemoresistance is induced by extracellular factors in tumor-bearing organs. By comparing chemosensitivity and proteins in different tumors (primary vs. metastases) and different culture systems (tumor fragment histocultures vs. monolayer cultures derived from the same tumor), we found elevated levels of acidic (aFGF) and basic (bFGF) fibroblast growth factors in the conditioned medium (CM) of solid and metastatic tumors. These CM induced broad spectrum resistance to drugs with diverse structures and action mechanisms (paclitaxel, doxorubicin, 5-fluorouracil). Inhibition of bFGF by mAb and its removal by immunoprecipitation resulted in complete reversal of the CM-induced chemoresistance, whereas inhibition͞removal of aFGF resulted in partial reversal. Using CM that had been depleted of aFGF and͞or bFGF and subsequently reconstituted with respective human recombinant proteins, we found that bFGF but not aFGF induced chemoresistance whereas aFGF amplified the bFGF effect. aFGF and bFGF fully accounted for the CM effect, indicating these proteins as the underlying mechanism of the chemoresistance. The FGF-induced resistance was not due to reduced intracellular drug accumulation or altered cell proliferation. We further showed that an inhibitor of aFGF͞bFGF (suramin) enhanced the in vitro and in vivo activity of chemotherapy, resulting in shrinkage and eradication of well established human lung metastases in mice without enhancing toxicity. These results indicate elevated levels of extracellular aFGF͞bFGF as an epigenetic mechanism by which cancer cells elude cytotoxic insult by chemotherapy, and provide a basis for designing new treatment strategies.R esistance of tumor cells to chemotherapy and the limited efficacy of chemotherapy in metastatic disease are two major challenges in patient management. A common resistance mechanism observed in preclinical studies is the overexpression of drug efflux proteins (1-3). However, clinical studies show that inhibition of the drug efflux proteins does not significantly improve the effectiveness of chemotherapy in patients (4, 5), suggesting the existence of other chemoresistance mechanisms.Using the transplantable, metastatic rat prostate MAT-LyLu tumor, we have shown that the antitumor activity of paclitaxel in lymph node metastases was 20-fold lower than in s.c. implanted primary tumors. When the metastatic tumor was reimplanted at the s.c. site, the resistance was lost in the second generation primary tumor but regained in the second generation metastases. We further found that the chemoresistance in metastatic tumors is not due to reduced intracellular drug accumulation or retention (6). These results led to the hypothesis of an epigenetic chemoresistance mechanism that is mediated by extracellular factors present in tumor-bearing organs. The present study tested the hypothesis, identified the factors that induce resistance, and determined the resto...
These results support a role of bFGF in paclitaxel resistance in human patient tumors.
Systemic chemotherapy is not effective in the treatment of prostate-confi ned cancer. We developed biodegradable, doxorubicin-loaded cylinders for intraprostatic implantation and evaluated the feasibility of using regional intraprostatic drug therapy to treat prostate-confi ned cancer. Cylinders were prepared using poly(lactide-co-glycolide) (PLG) or PLG co polymers. The in vitro and in vivo drug release, intraprostatic pharmacokinetics, and histopathology in dogs implanted with the cylinders were studied. The doxorubicin-loaded cylinders made of PLG polymers of 7.9 to 54 kDa molecular weight (MW) had a diameter of ~800 m m, drug loading of 10% to 30% (wt/wt), and even distribution of crystalline drug throughout the matrix. Burst release varied from 3% to 73%, and 7-day cumulative release from 4% to 90%. Decreasing polymer MW and increasing drug loading were associated with higher initial burst release and overall release rates. The in vivo drug release from cylinders (33-kDa PLG, 30% drug loading) in dog prostates was rapid (~80% in 48 hours). Spatial drug distribution, visualized using confocal fl uorescence microscopy, showed high concentrations confi ned to the lobule containing the implant (referred to as the implanted lobule), with steep concentration gradients over the septa separating the lobules. Concentrations in the implanted lobule were about 8 times higher than concentrations delivered by an intravenous injection. The implants caused necrotic cell death in the implanted lobule, without damage to prostatic nerve bundles or the urethra. These results indicate the feasibility of using biodegradable PLG cylinders as intraprostatic implants to selectively deliver high drug concentrations to prostate tissue.
Purpose:The present study evaluated the tissue distribution and targeting advantage of intraprostatic chemotherapy. Experimental Design: We studied the delivery and spatial distribution of a fluorescent drug, doxorubicin, in the prostate of beagle dogs, after intraprostatic or i.v. administration. Drug concentrations were measured using high-performance liquid chromatography and confocal fluorescence microscopy. Results: I.v. and intraprostatic injections yielded qualitatively and quantitatively different doxorubicin distribution in the prostate. A relatively homogeneous distribution was found after i.v. administration, whereas intraprostatic injection yielded a highly heterogeneous distribution with >10-fold higher concentrations localized in a cone-shaped glandular lobule bound by fibromuscular stroma, compared with other parts of the prostate. Compared with i.v. injection, intraprostatic injection yielded, on average, f100-fold higher tissue-to-plasma concentration ratio, ranging from 963-fold near the injection site to 19-fold in the contralateral half of the prostate. The drug distribution within the prostate further suggests an important role for acinar flow in intraprostatic drug transport. Conclusions: Intraprostatic administration represents a viable option to deliver high drug concentrations within the prostate. The results further suggest the fibromuscular stroma separating the prostatic lobules as a major barrier to drug transport and convective flow as an important drug transport mechanism in the prostate.
The two known mechanisms for telomere maintenance in eukaryocytes are telomerase in telomerase-positive cells and alternative lengthening of telomeres (ALT) in telomerase-negative cells. We report here that telomere maintenance in the telomerase-positive human ovarian SKOV-3 cells was not a¡ected by inhibition of telomerase. For comparison, the e¡ect of telomerase inhibitors on telomere maintenance in another telomerase-positive cell line (i.e. human pharynx FaDu cells) and the telomerase-negative human osteosarcoma Saos-2 cells was examined. Telomerase activity was measured using a modi¢ed telomeric repeat ampli¢cation protocol and telomere length was measured using a solution hybridization-based method and £uorescence in situ hybridization. A reverse transcriptase inhibitor (3P P-azido-deoxythymidine or AZT) and an antisense against a component of human telomerase RNA (antisense hTR) were used to inhibit telomerase. FaDu and SKOV-3 cells showed comparable baseline telomerase activity. Telomerase activity in both cells was inhibited about equally by AZT (maximal inhibition of V V80%) and by expression of antisense hTR (complete inhibition in SKOV-3 cells and maximal inhibition of V V80% in FaDu cells). However, treatment with telomerase inhibitors resulted in V V50% telomere shortening in FaDu cells but had no e¡ect on SKOV-3 nor Saos-2 cells. SKOV-3 cells did not show the characteristic features of ALT (i.e. heterogeneous telomere length and promyelocytic leukemia bodies), whereas these ALT features were observed in Saos-2 cells. Collectively, these results suggest the existence of a telomerase-independent mechanism of telomere maintenance in the telomerase-positive SKOV-3 cells. ß
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