Article

The safety of synthetic paclitaxel by intralesional delivery with OncoGeltrade mark into skin breast cancer metastases: method and results of a clinical pilot trial.

Authors:
To read the full-text of this research, you can request a copy directly from the authors.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the authors.

Chapter
Peutz-Jeghers SyndromeMuir-Torre SyndromeNeurofibromatosisGlucagonoma SyndromeFlorid Cutaneous PapillomatosisThe sign of Leser-Tr ElatAcanthosis NigricansCutaneous Radiation Damage Overlying the Thyroid, Breasts, and other SitesAcute Neutrophilic DermatosisAcquired IchthyosisHypertrichosis Lanuginosa AcquisitaConclusion References
Article
Implantable, biocompatible and biodegradable devices bearing an anticancer drug can provide promising local therapy to patients with malignant disorders. With the aim of treating brain tumors, especially gliomas, a membranous sheet containing doxorubicin was produced by co-polymerization to poly(D,L-lactide-co-glycolide) (PLGA). When release of the drug from the sheet was measured, sustained release continued until day 34. The data contrasted with the burst release from material containing a higher proportion of the drug. In terms of biodegradability, a subcutaneous 3 x 3-mm tetragonal sheet was almost completely absorbed by day 80. When a glioma was implanted subcutaneously and the tumor nodule exposed to the sheet, the device inhibited tumor growth significantly. The sheet consisted of an amorphous structure with cavities estimated to have a diameter of 0.5 - 3 microm by electron microscopic observation. Since the sheet is implantable, biodegradable and has a sustained-drug release property, the device may play a role in the local therapy of brain tumors.
Article
Better known as Taxol (Bristol-Myers Squibb), paclitaxel is the first member of the taxane family to be used in cancer chemotherapy. The taxanes exert their cytotoxic effect by arresting mitosis through microtubule stabilization, resulting in cellular apoptosis. The use of paclitaxel as a chemotherapeutic agent has become a broadly accepted option in the treatment of patients with ovarian, breast and non-small cell lung cancers, malignant brain tumors, and a variety of other solid tumors. However, significant toxicities, such as myelosuppression and peripheral neuropathy, limit the effectiveness of paclitaxel-based treatment regimens. This review addresses the toxicities associated with paclitaxel treatment and describes existing and future strategies of paclitaxel administration directed at limiting these toxicities.
Article
Full-text available
Interleukin-12 (IL-12) has been shown to possess potent immunoregulatory and antitumoral effects. We have evaluated the anti-oncogenic potential and the mechanisms of the antitumoral effect of in vivo adenovirus-mediated transfer of IL-12 gene in a murine model of colon cancer. AdCMVIL-12 was constructed to permit coordinated production of p40 and p35 subunits of IL-12 gene to obtain the maximum IL-12 bioactivity. Infection of murine colon cancer CT-26 cells in vitro with AdCMVIL-12 resulted in the production of high levels of IL-12. In vivo gene therapy of colon cancer nodules by intratumoral injection of AdCMVIL-12 induced a local increase in IL-12 and interferon-gamma levels and a complete regression of the tumor in 26 of 34 (76%) mice. Tumor disappeared between days 7 and 10 after vector administration. The antitumoral effect was mediated by CD8+ T cells and was associated with the generation of cytotoxic T lymphocytes against colon cancer cells. Animals that eliminated the tumor were protected against a second administration of neoplastic cells. Treatment with AdCMVIL-12 of one tumor nodule also caused regression of established tumors at distant sites. These data demonstrate that AdCMVIL-12 is a useful therapeutic tool for established colon cancer in mice and should be considered for application in humans.
Article
Full-text available
Direct gene transfer offers the potential to introduce DNA encoding therapeutic proteins to treat human disease. Previously, gene transfer in humans has been achieved by a cell-mediated ex vivo approach in which cells from the blood or tissue of patients are genetically modified in the laboratory and subsequently returned to the patient. To determine the feasibility and safety of directly transferring genes into humans, a clinical study was performed. The gene encoding a foreign major histocompatibility complex protein, HLA-B7, was introduced into HLA-B7-negative patients with advanced melanoma by injection of DNA-liposome complexes in an effort to demonstrate gene transfer, document recombinant gene expression, and determine the safety and potential toxicity of this therapy. Six courses of treatment were completed without complications in five HLA-B7-negative patients with stage IV melanoma. Plasmid DNA was detected within biopsies of treated tumor nodules 3-7 days after injection but was not found in the serum at any time by using the polymerase chain reaction. Recombinant HLA-B7 protein was demonstrated in tumor biopsy tissue in all five patients by immunochemistry, and immune responses to HLA-B7 and autologous tumors could be detected. No antibodies to DNA were detected in any patient. One patient demonstrated regression of injected nodules on two independent treatments, which was accompanied by regression at distant sites. These studies demonstrate the feasibility, safety, and therapeutic potential of direct gene transfer in humans.
Article
Full-text available
The single biggest challenge now facing drug delivery (for liposomes and indeed other carriers) is to initiate and produce release of the encapsulated drug only at the diseased site and at controllable rates. Our efforts have focused on developing a new thermal-sensitive drug delivery system, specifically for the local control of solid tumors. We describe here a new lipid formulation containing doxorubicin that has been optimized for both mild hyperthermic temperatures (39 degrees C to 40 degrees C) that are readily achievable in the clinic and rapid release times of drug (tens of seconds). This new liposome, in combination with mild hyperthermia, was found to be significantly more effective than free drug or current liposome formulations at reducing tumor growth in a human squamous cell carcinoma xenograft line (FaDu), producing 11 of 11 complete regressions lasting up to 60 days posttreatment.
Article
Full-text available
Paclitaxel has been proven to be effective against different types of cancer. A delivery system loaded with paclitaxel at tumor site should provide a high local concentration of the drug detrimental to malignant cells, which prevents the re-growth and metastasis of tumor. In this review, paclitaxel formulations for systemic and for intratumoral administration are discussed.
Article
Chemotherapy for brain tumours has been limited because of difficulty in achieving adequate exposure to the tumour without systemic toxicity. We have developed a method for local sustained release of chemotherapeutic agents by their incorporation into biodegradable polymers. Implantation of the drug-impregnated polymer at the tumour site allows prolonged local exposure with minimal systemic exposure. We conducted a randomised, placebo-controlled, prospective study to evaluate the effectiveness of biodegradable polymers impregnated with carmustine to treat recurrent malignant gliomas. In 27 medical centres, 222 patients with recurrent malignant brain tumours requiring re-operation were randomly assigned to receive surgically implanted biodegradable polymer discs with or without 3·85% carmustine. Randomisation balanced the treatment groups for all of the prognostic factors examined. Median survival of the 110 patients who received carmustine polymers was 31 weeks compared with 23 weeks for the 112 patients who received only placebo polymers (hazard ratio=0·67, p=0·006, after accounting for the effects of prognostic factors). Among patients with glioblastoma, 6-month survival in those treated with carmustine-polymer discs was 50% greater than in those treated with placebo (mortality=32 of 72 [44%] vs 47 of 73 [64%], p=0·02). There were no clinically important adverse reactions related to the carmustine polymer, either in the brain or systemically. Interstitial chemotherapy delivered with polymers directly to brain tumours at the time of surgery seems to be a safe and effective treatment for recurrent malignant gliomas
Article
Previously we described that the adoptive transfer of tumor-infiltrating lymphocytes (TIL) + interleukin-2 (IL-2) leads to eradication of established methyl cholanthrene (MCA)-105 fibrosarcoma pulmonary metastases in a congenic murine model. The in vivo efficacy of TIL was associated with their ability to secrets interferon-gamma (IFN-gamma), and to a lesser extent granulocyte-macrophage colony-stimulating factor. The local secretion of these cytokines resulted in recruitment of naive host immune cells to the tumor and eventually in a successful host antitumor immune response. In the present study, to further evaluate the role of IFN-gamma in the induction of a host antitumor immune response, we compared the treatment efficacy of adoptively transferred T cells and IFN-gamma gene transfected tumor cells (MCA-105/IFN-gamma) as delivery systems of IFN-gamma. Treatment with TIL-IL-2 or irradiated MCA-105/IFN-gamma induced a similar reduction in pulmonary metastases of MCA-105 tumor. In contrast, irradiated wild-type MCA-105 or TIL from IFN-gamma gene knockout mice did not cause tumor eradication. MCA-105 tumor-bearing mice treated with MCA-205/IFN-gamma showed a partial reduction in the number of pulmonary metastases. Histologically, lungs of successfully treated mice showed that initially activated macrophages expressing inducible nitric oxide synthase (iNOS) and dendritic cells infiltrated the tumor bed. Subsequently, CD4(+) and CD8(+) T cells infiltrated tumors. The therapeutic efficacy of IFN-gamma transfected tumor cells was eliminated when either CD4(+) T cells or CD8(+) T cells were depleted. These results suggest that local secretion of IFN-gamma induces a tumor-specific host antitumor immune response mediated through activated macrophages, dendritic cells, and tumor-specific T cells. This may be a common component of successful immunotherapy.
Article
Effect of temperature shift during culture period on cell growth and paclitaxel was investigated to optimize paclitaxel production in suspension culture of Taxus chinensis. Cell growth showed the optimum at 24°C while paclitaxel synthesis showed the maximum at 29°C. To minimize the inhibitory effect of higher temperature on cell growth, temperature was shifted after a certain period of culture time at 24°C. Paclitaxel synthesis in plant cell culture increased dramatically during day 14 to day 21 regardless of treatment, reaching the maximum production of 137.5 mg paclitaxel/L. When the temperature was maintained at 29°C after day 21, the specific productivity of paclitaxel was sustained for prolonged period of 42 days. The possible relationship between temperature and paclitaxel synthetic pathway was also suggested.
Article
We attempted to originate a nonsurgical treatment alternative for cutaneous squamous cell carcinoma (SCC), and we evaluated intratumoral modified-release chemotherapy with fluorouracil/epinephrine injectable gel (5-FU/epi gel). To assess the safety and efficacy, we conducted an open-label pilot study of 5-FU/epi gel in 25 patients with biopsy-proven SCC lesions on the face, head, neck, trunk, arms, and hands. Each tumor site was injected intradermally with up to 1.0 ml of 5-FU/epi gel. One SCC per patient was treated weekly for up to 6 weeks, then observed for 4 months at which time the tumor site and margins were excised for histologic examination. Overall, 96% (22 of 23) of evaluable treated tumors had histologically confirmed complete tumor clearing. No clinically significant systemic reactions or unexplained treatment-related adverse medical events occurred. The evaluations of the cosmetic appearance of the treated sites, judged subjectively by clinicians and patients, were mostly good to excellent and generally in close agreement. Treatment of superficial SCC with 5-FU/epi injectable gel results in a high rate of histologically confirmed complete tumor responses and may provide a nonsurgical treatment alternative in selected patients.
Article
Ethical considerations in a cancer phase I trial require a design allowing determination of the maximum tolerated dose with a minimum number of patients treated at low ineffectual or high overly toxic doses. It would also be advantageous to complete the phase I trial in as short a period of time and with as few patients as possible to allow further resources for later studies in which patients are treated at the optimal dose. Several dose escalation schemes are compared. These are the Fibonacci, two two-stage schemes, and a proposed scheme which uses knowledge of all toxicity grades. Estimates of the maximum tolerated dose are obtained and compared using the dose escalation schemes alone, a logit model, and a proposed mean response model. Confidence intervals using the delta method are obtained from the logit and mean response models. The proposed scheme and the two-stage schemes have the advantage of requiring fewer patients, particularly at low doses. Confidence intervals obtained from the mean response model have better coverage than those from the logit model. Data from a cancer phase I trial of dipyridamole and acivicin is presented to illustrate the methods.
Article
Methodological aspects of planning and evaluating phase I studies in oncology--the link between preclinical research and approval of clinical efficacy--include the human starting dose, maximum tolerable dose and dose escalation schemes. Statistical requirements of phase I studies are presented here, emphasizing the urgency of their application in current practice. For the maximum tolerable dose a distinction will be made between an individual- and a population-based approach, which is crucial for a correct definition and statistical parameter estimation. Weaknesses of the dose escalation scheme according to the modified Fibonacci scheme are shown and contrasted with the recently proposed pharmacokinetically guided dose escalation. Comprehensive phase I/II information processing is recommended for validating current practice.
Article
Chemotherapy for brain tumours has been limited because of difficulty in achieving adequate exposure to the tumour without systemic toxicity. We have developed a method for local sustained release of chemotherapeutic agents by their incorporation into biodegradable polymers. Implantation of the drug-impregnated polymer at the tumour site allows prolonged local exposure with minimal systemic exposure. We conducted a randomised, placebo-controlled, prospective study to evaluate the effectiveness of biodegradable polymers impregnated with carmustine to treat recurrent malignant gliomas. In 27 medical centres, 222 patients with recurrent malignant brain tumours requiring re-operation were randomly assigned to receive surgically implanted biodegradable polymer discs with or without 3.85% carmustine. Randomisation balanced the treatment groups for all of the prognostic factors examined. Median survival of the 110 patients who received carmustine polymers was 31 weeks compared with 23 weeks for the 112 patients who received only placebo polymers (hazard ratio = 0.67, p = 0.006, after accounting for the effects of prognostic factors). Among patients with glioblastoma, 6-month survival in those treated with carmustine-polymer discs was 50% greater than in those treated with placebo (mortality = 32 of 72 [44%] vs 47 of 73 [64%], p = 0.02). There were no clinically important adverse reactions related to the carmustine polymer, either in the brain or systemically. Interstitial chemotherapy delivered with polymers directly to brain tumours at the time of surgery seems to be a safe and effective treatment for recurrent malignant gliomas.
Article
Sustained drug delivery by biodegradable polymer devices can increase the therapeutic efficacy of drugs by producing high local tissue concentrations over extended periods of time. It has been shown previously that implantation of controlled-release polymers impregnated with the nitrosourea carmustine (BCNU) extended the period of survival in rats bearing the 9L glioma compared with similar rats treated with systemically administered BCNU. This study evaluated the effect on the monkey brain of interstitial delivery of BCNU by the biodegradable polyanhydride copolymer poly[bis(p-carboxyphenoxy)propane]anhydride (PCPP) and sebacic acid (SA) in a 20:80 formulation (PCPP:SA). The effect of combining interstitial BCNU with radiation therapy was also evaluated. Eighteen male cynomolgus monkeys were randomly assigned to one of four groups: a control group; a group with implantation of empty polymer; a group with implantation of BCNU-loaded polymer; and a group with implantation of empty polymer in the right hemisphere and BCNU-loaded polymer in the left hemisphere, followed by irradiation. The effects were evaluated radiologically and histologically at specified times. A local reaction by the brain to the polymer was found, which was greater when the polymer contained BCNU. Local cerebral edema was observed radiographically on postoperative Day 14 and had resolved by Day 72. Histologically, a subacute cellular inflammatory response was seen on postoperative Day 16, which had changed to a chronic inflammatory response by Day 72. In the group with radiation therapy administered to the hemisphere bearing BCNU-loaded polymer, only localized pathological changes were detected. In all animals, brain distant from the polymer implantation site was normal. No neurological or general deleterious effects were seen in any of the animals. It is concluded that the interstitial delivery of BCNU by the polyanhydride polymer PCPP:SA is safe in the primate brain and that concomitant radiation therapy did not lead to any adverse effects. These experimental findings are important to an understanding of the clinical effects of PCPP:SA implants in treating brain diseases.
Article
Platinum compounds are thought to be concentration- and time-dependent, but intravenous (i.v.) administration does not afford prolonged high platinum concentration in tumor tissue. In order to examine the influence of long-term local continuous (LC) injection of carboplatin, a pharmacokinetic study was performed. Twenty-six patients with uterine cancer were included. I.v. administration (11 patients): carboplatin (210 mg) was given i.v. and samples of target tissue were obtained at operation about 2 or 24 h after administration. LC administration (15 patients): the 21-gauge needle was implanted at the uterine cervix, and carboplatin was injected continuously (30 mg/day) for 3, 7 or 14 days using an external pump. The tissue platinum concentration was measured in the pelvic organs. The mean platinum levels at the cervix and vaginal wall in the LC (7 days) group were higher than those in the i.v. (2 h) group (p < 0.01). With LC injection, sustained platinum levels were maintained in the pelvic organs for a long time, with very few side effects. LC injection may be advantageous on the basis of pharmacokinetics.
Article
Development of new drugs requires a thorough investigation of efficacy and safety of pharmaceuticals. The potential risks and benefits of drugs used in chemotherapy are carefully considered such that the benefits of using a new drug outweigh the risks in terms of the side effects caused by the drug. Damage to normal cells, tissues, organs and/or the whole organism is a big concern. Several tests are now routinely performed and are required for drug approval by various regulatory agencies around the globe. The primary goals of such preclinical safety evaluation of drugs are: (1) to identify an initial safe starting dose and subsequent dose escalation scheme to humans; (2) to identify potential target organs of toxicity and reversibility of toxicity; (3) to identify potential damage to the genetic material (genotoxicity); and (4) to identify parameters of clinical monitoring. In this paper, various models for genotoxicity assays are presented. These include: Ames assay, in vitro chromosome aberration assay and an in vivo micronucleus assay. New technologies, such as DNA adduct formation, DNA strand breakage, apoptotic changes, p53 gene expression and transgenic animal models, are also considered.
Article
We describe an adaptive dose escalation scheme for use in cancer phase I clinical trials. The method is fully adaptive, makes use of all the information available at the time of each dose assignment, and directly addresses the ethical need to control the probability of overdosing. It is designed to approach the maximum tolerated dose as fast as possible subject to the constraint that the predicted proportion of patients who receive an overdose does not exceed a specified value. We conducted simulations to compare the proposed method with four up-and-down designs, two stochastic approximation methods, and with a variant of the continual reassessment method. The results showed the proposed method effective as a means to control the frequency of overdosing. Relative to the continual reassessment method, our scheme overdosed a smaller proportion of patients, exhibited fewer toxicities and estimated the maximum tolerated dose with comparable accuracy. When compared to the non-parametric schemes, our method treated fewer patients at either subtherapeutic or severely toxic dose levels, treated more patients at optimal dose levels and estimated the maximum tolerated dose with smaller average bias and mean squared error. Hence, the proposed method is promising alternative to currently used cancer phase I clinical trial designs.
Article
Despite improved systemic control of metastatic breast cancer, the incidence of brain metastases from breast carcinoma continues to rise, in part because most systemically administered agents have poor central nervous system penetration. Therefore, as a method of optimizing drug delivery into the central nervous system, we studied the safety and efficacy of chemotherapy delivered locally via biodegradable polymers in a mouse model of breast carcinoma metastases to the brain. The chemotherapeutic agents carmustine (BCNU), carboplatin, and camptothecin were incorporated into controlled release polymers and tested individually against intracranial challenges of EMT-6 breast tumor in BALB/c female mice. For each drug, four groups were tested: Group 1, empty polymer (no drug); Group 2, external beam radiotherapy (XRT) alone; Group 3, local chemotherapy from biodegradable polymer alone; and Group 4, local chemotherapy and XRT together. Polymers were implanted 5 days after intracranial tumor inoculation; XRT was administered on Days 7 through 9 (300 cGy/d). BCNU polymer alone (n = 10; median survival time, >200 d; P < 0.0001) and BCNU and XRT together (n = 10; median survival time, 41 d; P = 0.02) significantly improved survival in mice with intracranial EMT-6 breast cancer in comparison with control animals (n = 20; median survival time, 17 d). Carboplatin and camptothecin, either with or without XRT, and XRT alone did not have any significant effect on survival. Local delivery of BCNU with biodegradable polymers can significantly prolong survival in a murine model of intracranial metastatic breast cancer. Surgical resection and placement of BCNU polymers into the resection cavity may decrease the incidence of local recurrence of breast cancer metastases with minimal morbidity.
Article
Previously we described that the adoptive transfer of tumor-infiltrating lymphocytes (TIL) + interleukin-2 (IL-2) leads to eradication of established methylcholanthrene (MCA)-105 fibrosarcoma pulmonary metastases in a congenic murine model. The in vivo efficacy of TIL was associated with their ability to secrete interferon-gamma (IFN-gamma), and to a lesser extent granulocyte-macrophage colony-stimulating factor. The local secretion of these cytokines resulted in recruitment of naive host immune cells to the tumor and eventually in a successful host antitumor immune response. In the present study, to further evaluate the role of IFN-gamma in the induction of a host antitumor immune response, we compared the treatment efficacy of adoptively transferred T cells and IFN-gamma gene transfected tumor cells (MCA-105/IFN-gamma) as delivery systems of IFN-gamma. Treatment with TIL-IL-2 or irradiated MCA-105/IFN-gamma induced a similar reduction in pulmonary metastases of MCA-105 tumor. In contrast, irradiated wild-type MCA-105 or TIL from IFN-gamma gene knockout mice did not cause tumor eradication. MCA-105 tumor-bearing mice treated with MCA-205/IFN-gamma showed a partial reduction in the number of pulmonary metastases. Histologically, lungs of successfully treated mice showed that initially activated macrophages expressing inducible nitric oxide synthase (iNOS) and dendritic cells infiltrated the tumor bed. Subsequently, CD4+ and CD8+ T cells infiltrated tumors. The therapeutic efficacy of IFN-gamma transfected tumor cells was eliminated when either CD4+ T cells or CD8+ T cells were depleted. These results suggest that local secretion of IFN-gamma induces a tumor-specific host antitumor immune response mediated through activated macrophages, dendritic cells, and tumor-specific T cells. This may be a common component of successful immunotherapy.
Article
New approaches to the treatment of head and neck cancer involve delivery of the therapeutic agent by direct injection into the tumor lesions. This locoregional therapy allows adaptation of conventional chemotherapy agents, such as bleomycin and cisplatin, to achieve higher drug concentrations in the tumor while avoiding severe systemic toxicities. Novel therapies administered through tumor injection, such as gene transfer, photosensitization, and biologic response modification, have been investigated in preclinical studies and are currently in different phases of clinical trial.
Article
Many biodegradable polymers were used for drug delivery and some are successful for human application. There remains fabrication problems, such as difficult processability and limited organic solvent and irreproducible drug release kinetics. New star-shaped block copolymers, of which the typical molecular architecture is presented, results from their distinct solution properties, thermal properties and morphology. Their unique physical properties are due to the three-dimensional, hyperbranched molecular architecture and influence microsphere fabrication, drug release and degradation profiles. We recently synthesized thermosensitive biodegradable hydrogel consisting of polyethylene oxide and poly(L-lactic acid). Aqueous solution of these copolymers with proper combination of molecular weights exhibit temperature-dependent reversible sol-gel transition. Desired molecular arrangements provide unique behavior that sol (at low temperature) form gel (at body temperature). The use of these two biodegradable polymers have great advantages for sustained injectable drug delivery systems. The formulation is simple, which is totally free of organic solvent. In sol or aqueous solution state of this polymer solubilized hydrophobic drugs prior to form gel matrix.
Article
To evaluate efficacy of a controlled-release cisplatin delivery system, used after marginal resection of mammary carcinoma (ie, resection of grossly evident tumor) in mice, to prevent tumor regrowth and metastasis. 42 female C3H-HeJ mice. Mice were inoculated with mammary carcinoma cells. Between 2 and 6 days later, tumors were marginally resected and mice were assigned to 1 of 3 groups: no treatment (control; n = 14), cisplatin administered intraperitoneally (i.p. cisplatin; 14), and cisplatin delivered by use of an open-cell polylactic acid system placed within the tumor bed (slow-release cisplatin; 14). Tumor regrowth was measured daily. Mice were euthanatized 14 days after surgery, and complete necropsies were performed. Tumor regrowth was not detected in the slow-release cisplatin group; however, tumor regrowth was detected in 7 of 14 mice in the i.p. cisplatin group and 14 of 14 mice in the control group. Median (+/-SD) number of days to tumor regrowth was 13.5+/-0.64 and 7.79+/-0.87 in the i.p. cisplatin and control groups, respectively. Mice in the i.p. cisplatin group had significantly delayed tumor regrowth, compared with control mice. Metastases to lungs were detected in 8 of 14 control mice but were not detected in mice in either cisplatin treatment group. The open-cell polylactic acid with cisplatin delivery system was successful in delaying local tumor regrowth and metastasis in mice with marginally resected mammary carcinoma. Use of a controlled-release cisplatin delivery system may be an effective adjunct treatment following excision of mammary carcinoma in humans and other animals.
Article
The efficacy of systemic chemotherapy for non-small cell lung cancer (NSCLC) has improved with newer agents. However, the response rates and prolonged survival times achieved by chemotherapy remain modest, and these small gains are obtained at the cost of significant toxicity. In this study, the efficacy of a controlled release formulation of paclitaxel was compared with conventional paclitaxel in animals with human lung cancer xenografts. Paclitaxel (10%) was encapsulated in a proprietary polymer in the form of microspheres (PACLIMER Delivery System). Tumor nodules comprised of two different cell lines (A549 and H1299) were treated by a single i.p. or intratumoral administration of conventionally formulated paclitaxel or a single intratumoral injection of the PACLIMER Delivery System. In vitro testing demonstrated that paclitaxel was released slowly from the microspheres with >80% released after 90 days. Direct comparison of the highest dose for all formulations (24 mg/kg) showed that for nodules comprised of either NSCLC cell line, growth of the PACLIMER Delivery System-treated nodules were inhibited significantly more than the groups treated with conventional paclitaxel or the vehicle controls. Tumor volume doubling times for A549 and H1299 nodules treated with PACLIMER Delivery System were 60 and 35 days, respectively, compared with 10 and 11 days, respectively, in the nodules treated with the conventional paclitaxel by intratumoral administration. We conclude that intratumoral administration of the PACLIMER Delivery System may substantially increase the efficacy of paclitaxel for the therapy of local-regional NSCLC.
Article
Microspheres from glycolide-L-lactide copolymers incorporating cisplatin (CDDP-MS) were prepared to evaluate the sustained release and anticancer effect by paratumoral injection on the gastric cancer with regional lymphnode metastases induced by VX2 tumor in rabbits. In the first set of experiment, the rabbits were divided into three groups subjected to treatment and compared the tissue cisplatin distribution. In the first group (CDDP-MS pt group), 1 mg/kg of cisplatin was administered by the method of paratumoral injection in the form of CDDP-MS. In the second group (CDDP solution pt group), the same dose was given in the form of CDDP aqueous solution in the same way and in the third group (CDDP solution i.v. group), the same dose was intravenously administered. In the second set of experiment, after twice of each therapy the anticancer effects were compared between CDDP-MS pt and CDDP solution i.v. groups. In results, the platinum concentrations of the tumor and regional lymphnodes were 3.14 +/- 6.22, 0.65 +/- 0.79 micrograms/g in the first group, 0.43 +/- 0.39, 0.16 +/- 0.16 microgram/g in the second group and 0.03 +/- 0.01, 0.07 +/- 0.05 microgram/g in the third group, respectively.
Article
We conducted a Phase 1 study to determine the maximal tolerated dose and maximum biologically active dose of the E1A gene delivered by intratumoral injection as a lipid complex with 3 beta[N-(n',n'-dimethylaminoethane)-carbamoyl] cholesterol/dioleoylphosphatidyl-ethanolamine (tgDCC-E1A). The E1A adenovirus gene functions as a tumor inhibitor gene by repressing oncogene transcription; modulating gene expression, resulting in cellular differentiation; and inducing apoptosis of cancer cells. E1A also sensitizes cancer cells to chemotherapeutic drugs such as etoposide, cisplatin, and taxol. Nine patients with recurrent and unresectable breast cancer and nine patients with head and neck cancer were enrolled. One tumor nodule in each patient was injected with tgDCC-E1A. Safety, tumor response, E1A gene transfer, and down-regulation of HER-2/neu were evaluated. No dose-limiting toxicity was observed in the four dose groups (15, 30, 60, and 120 microg DNA/cm of tumor). All patients tolerated the injections, although several experienced pain and bleeding at the injection site. A maximally tolerated dose was not reached in this study. E1A gene transfer was demonstrated in 14 of 15 tumor samples tested, and down-regulation of HER-2/neu was demonstrated in two of the five patients who overexpressed HER-2/neu at baseline. HER-2/neu could not be assessed in other posttreatment tumor samples because of extensive necrosis. In one breast cancer patient, no pathological evidence of tumor was found on biopsy of the treated tumor site at week 12. In 16 patients evaluable for tumor response, 2 had minor responses, 8 had stable disease, and 6 had progressive disease. Gene therapy with an E1A gene:lipid complex appears to be safe and warrants further testing.
Article
Release of several drugs from new ABA-type biodegradable thermal gels, ReGel, including proteins and conventional molecules, are presented. These are biodegradable, biocompatible polymers that demonstrate reverse thermal gelation properties. Organic solvents are not used in the synthesis, purification, or formulation of these polymers. The unique characteristics of ReGel hinge on the following two key properties: (1) ReGel is a water soluble, biodegradable polymer at temperatures below the gel transition temperature; (2) ReGel forms a water-insoluble gel once injected. This is consistent with a hydrophobically bonded gel state where all interactions are physical, with no covalent crosslinking. An increase in viscosity of approximately 4 orders of magnitude accompanies the sol--gel transition. The gel forms a controlled release drug depot with delivery times ranging from 1 to 6 weeks. ReGel's inherent ability to solubilize (400 to >2000-fold) and stabilize poorly soluble and sensitive drugs, including proteins is a substantial benefit. The gel provided excellent control of the release of paclitaxel for approximately 50 days. Direct intratumoral injection of ReGel/paclitaxel (OncoGel) results in a slow clearance of paclitaxel from the injection site with minimal distribution into any organ. Efficacies equivalent to maximum tolerated systemic dosing were observed at OncoGel doses that were 10-fold lower. Data on protein release (pGH, G-CSF, insulin, rHbsAg) and polymer biocompatibility are discussed.
Article
Will amifostine (A) protect against chemotherapy-induced neuro- and myelotoxicity. Ninety ovarian cancer patients were randomized to receive standard paclitaxel + carboplatin without (PC) or preceded by amifostine 740 mg/m(2) (PC + A). The mean baseline values of hemoglobin, leukocyte, and platelets were slightly lower in the amifostine group, but the mean percentual decrease of these parameters after each treatment cycle showed no difference between both arms. Symptoms of neurotoxicity remained absent in 40% PC vs. 49% PC + A cycles; sensory neurotoxicity grade I occurred in 45% vs. 48% and grade II in 12% PC vs. 2% of PC + A cycles (overall P < 0.001). Nausea grade II was reported in 2% vs. 6% (P = 0.007) and vomiting grade II in 1% of PC vs. 8% PC + A cycles (P < 0.001). Amifostine was temporarily interrupted in five patients due to hypotension, but no dose reductions were indicated. Quality of life questionnaires showed no difference in neurotoxicity scores between both study arms at treatment completion. The median progression-free survival was 16 vs. 22 months (n.s.) for PC and PC + A patients. In a pooled analysis of four randomized studies, amifostine diminished the risk of developing neurotoxicity grade II-III (Odds Ratio 0.3, 95% confidence interval 0.15-0.63, P < 0.05), but had no effect on the risk for bone marrow toxicity. Amifostine shows only minor but significant activity in diminishing neurotoxicity without preventing paclitaxel + carboplatin-induced bone marrow toxicity.
Article
Squamous cell carcinoma is one of the most common primary cutaneous carcinomas but on rare occasion, metastatic squamous cell carcinoma from a distant site or solid organ can present as a cutaneous lesion. Most metastases occur as dermal nodules or involve the dermal lymphatics, but when they are intimately associated with the epidermis, distinguishing the lesion as primary or metastatic may be extremely difficult and usually requires a clinical history or high index of suspicion. A 71-year-old woman presented with multiple eruptive nodules over her chest, flank, and back. Histologically the lesions appeared to be arising from the surface epithelium and consisted of atypical, predominantly spindle cells, some of which streamed off of the epidermis. Following the initial evaluation, a history of breast carcinoma with subsequent radiation therapy and ultimate mastectomy was obtained, and the original breast biopsy and mastectomy material was reviewed. After performing additional studies, it became clear that the origin of the carcinomas was metastatic from an underlying metaplastic breast carcinoma.