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Biomedical subjects

D J Garcia

Publications and source records attributed to D J Garcia.

10 recordsLinked to original sources
PubMed2004

Spin order in one-dimensional Kondo and Hund lattices.

We study numerically the one-dimensional Kondo and Hund lattices consisting of localized spins interacting antiferromagnetically or ferromagnetically with the itinerant electrons, respectively. Using the density-matrix renormalization group we find, for both models and in the small coupling regime, the existence of new magnetic phases where the local spins order forming ferromagnetic islands coupled antiferromagnetically. Furthermore, by increasing the interaction parameter |J| we find that this order evolves toward the ferromagnetic regime through a spiral-like phase with longer characteristic wavelengths. These results shed new light on the zero temperature magnetic phase diagram for these models.

Journal Article↗
PubMed2001

Phase I pharmacokinetic trial and correlative in vitro phase II tumor kinetic study of Apomine (SR-45023A), a novel oral biphosphonate anticancer drug.

PURPOSE: To study the human pharmacokinetics and in vitro cytotoxicity of Apomine, an p.o. administered, nonmyelosuppressive agent that selectively inhibits cell proliferation and induces tumor cell apoptosis through the farnesoid X receptor. EXPERIMENTAL DESIGN: Seven solid cancer patients who participated in an ongoing Phase I study of Apomine and received the starting dose level of 125 mg/m(2)/day x 14 days every 3 weeks underwent a pharmacokinetic study on day 14 of the first course. Plasma concentrations of Apomine were assayed with a Hewlett Packard gas chromatograph using a nitrogen phosphorus detector and HP-5 15m x 0.32-mm column. Fresh human ovarian cancer tumor samples were obtained during initial exploratory laparotomy from 35 chemotherapy-naive, advanced stage epithelial ovarian cancer patients. Tumor samples were tested for sensitivity to Apomine, carboplatin, cisplatin, paclitaxel, and topotecan using an in vitro clonogenic [(3)H]thymidine end point assay. RESULTS: Pharmacokinetic analysis revealed a mean Apomine plasma C(max) of 16.4 +/- 9.1 microg/ml (29.1 microM), a mean plasma AUC(0--12 h) of 173.4 +/- 105 microg. h/ml (308 microM. h), and a mean t(1/2 (24--192 h)) of 156.2 +/- 42.9 h. In vitro assay results showed that 63 and 91% of the ovarian cancers were sensitive (i.e., >70% inhibition of tumor cell growth) to Apomine at concentrations of 10 and 20 microM. The sensitivity rates were 91% for carboplatin (270 microM), 88% for cisplatin (33 microM), 41% for paclitaxel (5.9 microM), and 85% for topotecan (2.2 microM). CONCLUSIONS: These in vitro assay results, taken together with our preliminary plasma pharmacokinetic data, suggest that Apomine should be clinically active at the 125 mg/m(2) dose level.

Administration, Oral↗
PubMed1997

In vitro phase II comparison of the cytotoxicity of a novel platinum analog, nedaplatin (254-S), with that of cisplatin and carboplatin against fresh, human ovarian cancers.

PURPOSE: To compare the in vitro cytotoxicity of nedaplatin, an investigational platinum analog, with that of the standard platinum agents, cisplatin and carboplatin, against fresh human, epithelial ovarian cancers. METHODS: The Hamburger-Salmon human tumor colony-forming assay (HTCA) was used to measure the chemosensitivity of 36 fresh tumor samples obtained during initial exploratory laparotomy from patients with newly diagnosed stage III-IV epithelial ovarian cancer who had received no prior chemotherapy or radiation therapy. Tumor samples were exposed to the platinum analogs for 1 h at concentrations of 10 and 100 micrograms/ml of nedaplatin and cisplatin and 100 and 1000 micrograms/ml of carboplatin. The resulting survival data were used to estimate the IC50 (drug concentration associated with 50% inhibition of tumor colony forming units, TCFUs) of each of the platinum analogs for each of the tumor samples, as well as the estimated survival following exposure to clinically achievable drug levels (i.e. the ultrafiltrable platinum area under the plasma disappearance curve, AUC, achieved in cancer patients following administration of standard or phase II doses). RESULTS: At the lowest concentration tested (i.e. 10 micrograms/ml nedaplatin and cisplatin and 100 micrograms/ml carboplatin) the percentages of tumor samples which were sensitive (as defined by 50% or less survival of TCFUs as compared with controls) were 42, 50, and 40% for nedaplatin, cisplatin and carboplatin, respectively. The median IC50 values were 28.5, 12 and 121 micrograms/ml for nedaplatin, cisplatin and carboplatin, respectively. The estimated percentage of tumors sensitive to clinically achievable dose levels was 42% for nedaplatin and 36% for cisplatin and carboplatin. Nedaplatin and carboplatin proved relatively crossresistant with cisplatin in vitro; of the 18 tumor samples which were resistant to cisplatin, only 5 (28%) were sensitive to nedaplatin and 3 of 17 (18%) were sensitive to carboplatin. CONCLUSION: Nedaplatin was associated with cytotoxicity similar to cisplatin and carboplatin in this study. Although nedaplatin appears to be crossresistant with cisplatin, its high rate of in vitro cytotoxicity, relative lack of neurotoxicity and nephrotoxicity, and large in vivo biovailability establish nedaplatin as a promising platinum analog for further clinical development as a salvage and primary chemotherapeutic agent for patients with advanced ovarian cancer.

Antineoplastic Agents↗
PubMed1997

Safety aspects of pegylated liposomal doxorubicin in patients with cancer.

Encapsulation in polyethylene glycol-coated (pegylated; Stealth) liposomes alters the pharmacokinetic characteristics, and hence the safety and tolerability profile, of doxorubicin. Pegylated liposomal doxorubicin administered as a single agent is generally well tolerated. Grade III/IV leucopenia, stomatitis and palmar-plantar erythrodysaesthesia affected 16, 6 and 18% of solid tumour patients, respectively. Other adverse effects included nausea and vomiting and alopecia. Acute hypersensitivity infusion reactions have been reported in up to 9% of patients in some studies. Recently published data from a phase II trial in patients with refractory ovarian cancer showed no alopecia or cardiotoxicity and little nausea and vomiting after pegylated liposomal doxorubicin. Unlike free doxorubicin, pegylated liposomal doxorubicin is not a vesicant. Preliminary data, not yet confirmed in comparative studies, suggest that the pegylated liposomal formulation may be less cardiotoxic than free doxorubicin. Mucositis, however, appears to be increased. Studies to determine optimal dosing schedules and safety of pegylated liposomal doxorubicin in combination with other agents are ongoing.

Antibiotics, Antineoplastic↗
PubMed1995

An overview of clinical cancer chemoprevention studies with emphasis on positive phase III studies.

Cancer prevention aims to halt or reverse the development and progression of precancerous cells through the use of noncytotoxic nutrients and/or pharmacologic agents during the lengthy time period between tumor initiation and frank malignancy. This paper reviews cancer chemoprevention studies and focuses on Phase III trials, which are large, randomized, placebo-controlled studies that usually last several years. Studies may include multiple agents and dose levels, long-term toxicity evaluations or the modulation of surrogate endpoint biomarkers. Sample sizes of individual studies vary depending on statistical concerns and the demographics of the subject population. Recent Phase III trials include several promising agents: retinol; the retinoids 13-cis retinoic acid, all-trans-retinoic acid and 4-hydroxyphenyl retinamide; beta-carotene; finasteride and tamoxifen. Because one of the many actions of retinoids is the induction of epidermal differentiation, clinical trials with this class of agents have largely been conducted in epithelial or squamous cell tumor types. Several Phase III studies that have targeted the reversal of premalignant lesions or the prevention of second primary tumors have shown promising positive results. In contrast, some studies have shown that chemopreventive agents may have limited activity against the recurrence or progression of cells that have already undergone malignant transformation. Thus, the role of chemoprevention appears to lie in reversal of the premalignant process rather than suppression of malignant growth.

Antineoplastic Agents↗
PubMed1994

In vitro drug testing of ovarian cancer using the human tumor colony-forming assay: comparison of in vitro response and clinical outcome.

The purpose of this study was to assess the prognostic value of in vitro drug chemosensitivity testing using the Hamburger-Salmon human tumor colony-forming assay (HTCA) in fresh tumor samples obtained from newly diagnosed patients with stage II-IV ovarian cancer undergoing maximum cytoreductive surgery and prior to platinum-based chemotherapy. The HTCA was performed on fresh ovarian cancers obtained from 93 patients at their initial exploratory laparotomy to evaluate in vitro sensitivity to cisplatin, carboplatin, and cyclophosphamide following a 1-hr drug exposure. Prospective clinical follow-up was performed on all patients with the primary study endpoints being pathologically proven complete response at second-look surgery and disease-free and overall survival durations. In vitro drug sensitivity was strongly dose-dependent. At a concentration of 5 micrograms/ml only 23% of tumor samples were sensitive (as defined by a > or = 50% decrease in tumor colony-forming units compared to controls) to cisplatin; 13% of tumors were sensitive to carboplatin at a concentration of 50 micrograms/ml and 11% to 4-OH-cyclophosphamide at a concentration of 1 microgram/ml. At doses which were 10 times the previously stated concentrations, the sensitivity rates to cisplatin, carboplatin, and 4-OH-cyclophosphamide increased to 72, 63, and 53%, respectively. Subjects were categorized as having drug-sensitive disease if HTCA results showed in vitro drug sensitivity to at least one of the agents used in their primary chemotherapy. Multivariate analysis failed to show any advantage in clinical response rate, progression-free interval, or survival duration for patients with drug-sensitive disease compared to drug-resistant disease; however, there was evidence of a trend toward an enhanced pathologically proven complete response rate in patients who had chemosensitive tumors in vitro. Second-look surgery was performed in 28 of 55 patients with optimal surgical resections and no clinical evidence of disease at the completion of their primary chemotherapy. Fifty percent (5/10) of patients with drug-sensitive disease achieved a pathologic complete response, while only 3/18 (17%) patients with drug-resistant tumors had a documented pathologic complete response (P = 0.13). As reported in other ovarian cancer studies, patient characteristics which were found to be significantly associated with survival were stage of disease (II-III vs IV), optimal primary surgical resection (i.e., < 1 cm2 residual tumor) vs suboptimal resection, clinical measurability of disease at initiation of chemotherapy, and response to primary chemotherapy. In conclusion, in vitro drug sensitivity, as measured by the HTCA, does not appear to be an independent prognostic factor for survival in patients with stage II-IV epithelial ovarian cancer who undergo standard treatment with tumor debulking surgery and primary platinum-based chemotherapy.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1994

Salvage chemotherapy in recurrent or refractory squamous cell cancer of the uterine cervix.

Squamous cell cancer of the cervix is a relatively drug-resistant tumor. Therefore, chemotherapy is predominantly reserved for cervical cancer patients with recurrent or refractory disease following surgery and/or radiation therapy or for patients who present with far advanced, incurable disease. Objective responses to salvage chemotherapy are generally short lived (4 to 6 months) with few patients surviving more than 1 year. Complete clinical remissions primarily occur at extrapelvic sites (eg, lung, lymph node, and soft tissue metastases). Bulky pelvic tumor in an area of prior irradiation remains largely refractory to further therapy. At present, no chemotherapy regimen has proven superior to single-agent cisplatin, which is associated with an approximately 30% objective response rate. The most effective nonplatinum agents appear to be doxorubicin, ifosfamide, mitolactol, and vincristine. Multiple studies have documented improved partial response rates with platinum-based multiagent chemotherapy, but no regimen has been associated with an improved survival duration. To improve the poor prognosis of this patient group, identification of new agents with at least equivalent activity to cisplatin is mandatory. The development of new platinum-based regimens using currently available agents is unlikely to substantially improve patient survival, although better palliative therapy may result from this approach.

Antineoplastic Agents↗
PubMed1994

Total platinum dose versus platinum dose intensification in ovarian cancer treatment.

Multiple in vitro and in vivo studies demonstrate the importance of platinum dose intensity in chemotherapy of advanced ovarian cancer. The relevant areas discussed in this report include (1) retrospective analysis of platinum dose intensity and outcome of ovarian cancer therapy, (2) in vitro human tumor cell line drug assay data, (3) fresh human ovarian tumor cloning data, (4) platinum pharmacokinetics with an emphasis on the relationship between the platinum concentration x time product and cytotoxicity, and (5) prospective clinical studies designed to test the importance of platinum dose intensity alone or platinum dose intensity and total dose. When attempting to design optimal platinum-based therapies for ovarian cancer, it is important to bear in mind the following considerations: (1) both platinum dose intensity and total dose should be increased; (2) to achieve exponential cytotoxicity (eg, up to 10-fold increases in tumor cell kill) by increasing the platinum dose, it is critical to select a platinum dose capable of overcoming inherent drug resistance; (3) carboplatin may be the platinum analogue of choice for dose intensification studies since, unlike cisplatin, it is rarely associated with cumulative nonhematologic toxicity (and as a result can be escalated up to five to six times the standard dose); and (4) the Calvert formula should be used for determining carboplatin dose to safely and accurately target desired drug exposure (as measured by the concentration x time product) and degree of hematologic toxicity.

Clinical Trials as Topic↗
PubMed1983

Influence of hypoxia on the metabolism and excretion of misonidazole by the isolated perfused rat liver--a model system.

The isolated perfused rat liver was evaluated as a model system for the characterization of misonidazole metabolism under hypoxic conditions. Misonidazole metabolism by livers perfused under aerobic conditions was also examined. The clearance of misonidazole was more than three times greater under anaerobic compared to aerobic conditions (4.94 +/- 1.56 vs 1.27 +/- 0.22 ml/min; means +/- S.D., N = 3). Misonidazole metabolites were detected only in the bile. Analysis of these metabolites by reverse-phase high performance liquid chromatography (HPLC) demonstrated that misonidazole metabolism was also qualitatively changed when anaerobic conditions were employed. Misonidazole beta-glucuronide was the major metabolite detected under aerobic conditions, but it was a minor metabolite in anaerobically perfused livers. The three major metabolites produced under anaerobic conditions were not characterized, but desmethyl misonidazole (RO-07-9963) and the 2-amino-imidazole derivative of misonidazole (1-[2-aminoimidazol-1-yl]-3-methoxy-2-propanol) were excluded as possible structures.

Animals↗