Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A phase I trial was performed to investigate the tolerability and efficacy of the novel nucleoside analogue gemcitabine in combination with cisplatin in the treatment of advanced non-small cell lung cancer. Both cisplatin and gemcitabine were administered as 30 min infusions weekly x 3 with a week of rest. There was one dose escalation of cisplatin from 25 mg/m2 (dose level 1) to 30 mg/m2 (in subsequent dose levels 2-5), such that the mean dose intensity for the weekly x 3 q 4 week cycle was 22.5 mg/m2/week which is close to that achieved with 100 mg/m2 bolus monthly. Gemcitabine was initiated at 1000 mg/m2 (dose levels 1 and 2) then escalated by 250 mg/m2/week to 1750 mg/m2 (dose level 5). Of 32 chemotherapy-naive patients entered (22 males, 10 females; median age 61 years, range 29-74 years), 11 had localized tumours (2 stage IIIa, 9 IIIb) and 21 had stage IV tumours with haematogenous metastases and a poor prognosis. Twenty-one patients had adenocarcinoma, 4 squamous cell carcinoma, 6 large cell undifferentiated tumors, and one had mixed squamous and adenocarcinoma. Dose-limiting toxicity was not seen in more than one patient in cycle 1 at any dose level. Grade 4 granulocytopenia and thrombocytopenia occurred more frequently with repeated dosing, necessitating dose reductions except at the lowest dose level (cisplatin 25 mg/m2, gemcitabine 1000 mg/m2). Non-haematological toxicity was mild and rapidly reversible. Cisplatin administration led to a higher frequency of nausea and vomiting than that seen with gemcitabine alone, but this was easily controlled with antiemetics. In the 28 patients evaluable, to date responses have been seen at most dose levels, with an overall response rate 35.7%. This phase I trial is ongoing and further dose escalation is intended to determine the MTD of gemcitabine.
 ...
PMID:Phase I trial of gemcitabine and cisplatin in advanced non-small cell lung cancer: a preliminary report. 869 17

The introduction of new drugs may offer significant hope for improvement in the treatment of breast cancer. They include new cytotoxic agents such as Taxanes, Topoisomerase inhibitor, MDR modulator, new hormone such as 3rd generation nonsteroidal aromatase inhibitor, pure antiestrogen for patients with refractory metastatic breast cancer and new bisphosphonates for those who have metastases to bone. Therefore, some reports evaluating such new drugs were reviewed. Japanese studies revealed response rate of Taxanes in the treatment of metastatic breast cancer as follows; Six out of 22 (27%) with 1 CR for 24 hours infusion, 21 out of 52 (34%) with 2 CR for 3 hours infusion of paclitaxel respectively, 21 out of 31 (41%) with 2 CR for 1 hour infusion, and 32 out of 72 (44%) with 5 CR for 1 hour infusion of Docetaxel, In addition, the MTD of the combination was reached at dose level with 60 mg/sqm of Docetaxel and 400 mg/sqm of cyclophosphamide. As regards hormone therapy, thirty four out of 176 (19%) with 5 CR were observed in phase II study of Fadrozol but results from the phase II study of 3rd generation aromatase inhibitor is not yet accomplished in Japan. However, any european reports did not show a difference in response rate in patients with tamoxifen refractory breast cancer between newer aromatase inhibitor and megasterol, and a good choice of hormones in the treatment of metastatic breast cancer appears to be difficult.
 ...
PMID:[New drugs in metastatic breast cancer--1997]. 935 Feb 35

Analyses were performed on 40 patients with TAG-72 expressing metastatic cancer who were entered into three phase II clinical trials. The dose selected was the maximum tolerated dose in phase I studies. Patients all had unresectable metastatic colon or prostate cancer and had recovered from prior therapies. Patients in trials #1 and #2 received 75 mCi/m2 131I-CC49 antibody whereas those in trial #3 received a total of 75 mCi/m2 with equal amounts of 131I-CC49 and 131I-COL-1. The three trials have resulted in a reproducible degree of reversible marrow suppression; 72.5% of patients experienced moderate or severe toxicity. Comparisons were made between demographic, clinical and pharmacokinetical variables and the grade of WBC toxicity, platelet toxicity and the sum of the two as total toxicity. Whole body radiation dose had a statistically significant relationship with platelet toxicity (r = 0.38, p = 0.015) and total toxicity (r = 0.34, p = 0.035). The bone marrow radiation dose is significantly related to all toxicity indicators with correlation coefficients with WBC and platelet toxicities of 0.47 (p = 0.002) and 0.34 (p = 0.033), respectively. Plasma half-life had the strongest correlation with WBC toxicity and combined toxicities. Multivariate models were developed to help describe the simultaneous effect of these variables on toxicity. The results show that the MTD dose was safely given to patients who varied in age, disease burden and degree of marrow compromise. This supports the contention that a fixed dose of radiolabeled antibody per body mass or m2 can be given to a diverse group of non-lymphoma patients with a predictable toxicity range.
 ...
PMID:Correlation of toxicity with treatment parameters for 131I-CC49 radioimmunotherapy in three phase II clinical trials. 1085 51

Most cancer patients die with metastatic disease, thus, good models that recapitulate the natural process of metastasis including a dormancy period with micrometastatic cells would be beneficial in developing treatment strategies. Herein we report a model of natural metastasis that balances time to complete experiments with a reasonable dormancy period, which can be used to better study metastatic progression. The basis for the model is a 4T1 triple negative syngeneic breast cancer model without resection of the primary tumor. A cell titration from 500 to 15,000 GFP tagged 4T1 cells implanted into fat pad number four of immune proficient eight week female BALB/cJ mice optimized speed of the model while possessing metastatic processes including dormancy and beginning of reactivation. The frequency of primary tumors was less than 50% in animals implanted with 500-1500 cells. Although implantation with over 10,000 cells resulted in 100% primary tumor development, the tumors and macrometastases formed were highly aggressive, lacked dormancy, and offered no opportunity for treatment. Implantation of 7,500 cells resulted in >90% tumor take by 10 days; in 30-60 micrometastases in the lung (with many animals also having 2-30 brain micrometastases) two weeks post-implantation, with the first small macrometastases present at five weeks; many animals displaying macrometastases at five weeks and animals becoming moribund by six weeks post-implantation. Using the optimum of 7,500 cells the efficacy of a chemotherapeutic agent for breast cancer, doxorubicin, given at its maximal tolerated dose (MTD; 1 mg/kg weekly) was tested for an effect on metastasis. Doxorubicin treatment significantly reduced primary tumor growth and lung micrometastases but the number of macrometastases at experiment end was not significantly affected. This model should prove useful for development of drugs to target metastasis and to study the biology of metastasis.
...
PMID:Development and characterization of a preclinical model of breast cancer lung micrometastatic to macrometastatic progression. 2487 64

Deaths from cancer are mostly due to metastatic disease that becomes resistant to therapy. A mainstay treatment for many cancers is chemotherapy, for which the dosing strategy is primarily limited by patient toxicity. While this MTD approach builds upon the intuitively appealing principle that maximum therapeutic benefit is achieved by killing the largest possible number of cancer cells, there is increasing evidence that moderation might allow host-specific features to contribute to success. We believe that a "Goldilocks Window" of submaximal chemotherapy will yield improved overall outcomes. This window combines the complex interplay of cancer cell death, immune activity, emergence of chemoresistance, and metastatic dissemination. These multiple activities driven by chemotherapy have tradeoffs that depend on the specific agents used as well as their dosing levels and schedule. Here we present evidence supporting the idea that MTD may not always be the best approach and offer suggestions toward a more personalized treatment regime that integrates insights into patient-specific eco-evolutionary dynamics.
 ...
PMID:Searching for Goldilocks: How Evolution and Ecology Can Help Uncover More Effective Patient-Specific Chemotherapies. 3293 22