Although the long-term cardiotoxic effects of cumulative doses of doxorubicin are well established, the short-term effects on cardiac function are uncertain. Therefore we examined the short-term ...effects of doxorubicin on left ventricular systolic and diastolic function following a total of 56 doses of doxorubicin in 15 patients with normal resting left ventricular function. Resting radionuclide ventriculography was performed 1 hour before and 4 hours after each dose of doxorubicin. Left ventricular ejection fraction increased significantly from 64 +/- 1% to 67 +/- 1% (p less than 0.001) after doxorubicin. In addition, peak ejection rate (p less than 0.005) and peak filling rate (p less than 0.0005) increased significantly following short-term doxorubicin administration. There was no relationship between either the individual or cumulative dose of doxorubicin and the acute ejection fraction, peak ejection rate, or peak filling rate response. Our data suggest that doxorubicin acutely increases left ventricular systolic and diastolic function.
A phase i clinical trial of didemnin B Stewart, James A.; Low, Jane B.; Roberts, John D. ...
Cancer,
15 December 1991, Letnik:
68, Številka:
12
Journal Article
Recenzirano
Odprti dostop
Didemnin B is a depsipeptide extracted from the marine tunicate Trididemnin cyanophorum. This agent is a potent inhibitor of L1210 growth in vitro and has activity against murine B16 melanoma, P388 ...leukemia, and M5076 sarcoma in vivo. The results of preclinical toxicologic tests demonstrated abnormalities in clotting parameters thought to be secondary to drug‐induced liver dysfunction. Thirty‐five patients with advanced cancer received didemnin B according to a 5‐day bolus schedule with dose levels ranging from 0.03 to 2.00 mg/m2/d. The dose‐limiting toxicity was nausea and vomiting. Sporadic elevation of the hepatic enzyme level occurred but was not dose limiting. Two patients had anaphylactic symptoms possibly related to the 5% polyoxyethylated castor oil (Cremophor EL, BASF, Ludwigshafen, Germany) vehicle during the drug infusion. Clinical bleeding was not observed and myelosuppression was not significant. No partial or complete tumor responses were seen. The recommended Phase II dose for the 5‐day schedule is 1.6 mg/m2/d. Cancer 68:2550–2554, 1991.
Trimetrexate (TMQ; NSC 352122) is a potent inhibitor of dihydrofolate reductase with good activity against murine i.p.-implanted B16 melanoma and colon 26 tumors. Preclinical antineoplastic activity, ...demonstrated schedule dependency, and data suggesting effectiveness against methotrexate-resistant cells prompted a Phase I clinical and pharmacokinetic study of trimetrexate using an i.v. daily x5 schedule. Forty-three good performance status patients were treated with 12 dose levels using daily doses varying from 0.5 to 15 mg/m2/d. Plasma and urine samples were obtained for pharmacokinetic analysis using a high-performance liquid chromatographic method. Myelosuppression was dose limiting and 15 mg/m2/d x5 was the maximum tolerated dose. White blood cell (WBC) and platelet toxicity were noted at doses of 1.6 mg/m2 and above. Median WBC and platelet nadirs occurred on approximately Days 11-12 with recovery by Days 15-18. Nonhematological toxicity included mucositis, nausea and vomiting, stomatitis, diarrhea, and rash. Evidence for antitumor activity was seen in seven patients. Trimetrexate elimination from plasma could be represented as either a bi- or triexponential process. Terminal elimination half-lives were in the range of 5-14 h in patients represented by a triexponential model. Approximately 10-20% of the dose administered was excreted in urine over a 24-h period. The recommended starting dose for patients in Phase II trials using the d x5 i.v. schedule is 8.0 mg/m2/d repeated every 21 days. Dose escalations may be possible depending on the extent of prior therapy and individual tolerance of the drug.
In the B16 murine melanoma model tumor growth has been shown to be slower in animals of advanced age. One feature associated with this slower growth has been prominent fibrosis demonstrated in ...biopsies of the tumor in older animals. We have performed experiments to examine the fibrotic response in young and old mice. In non-tumor bearing animals the capacity to regain skin strength after surgical laceration and healing by primary intention was greater in old mice. Histologic preparations suggested a more prominent fibrosis at the wound site. The animals who were injected subcutaneously with B16 melanoma and treated with L 3,4-dehydroproline (an inhibitor of collagen synthesis) local tumor growth was significantly enhanced only for the old animals. Although this inhibition of collagen synthesis produced a differential growth enhancement, there remained a significant difference in tumor volume between young and old animals. We conclude that fibrogenesis is an important host defense for containing local tumor growth and that this mechanism is preserved if not enhanced in mice of advanced age. Nevertheless other factors are needed to account completely for the observed age-advantage in the B16 melanoma model.
The antibody response to a variety of antigens has been shown to diminish with age. We investigated the capacity for Thymosin Alpha One (T alpha 1) treatment to augment antibody production in tetanus ...toxoid (TT) and pneumococcal capsular polysaccharide (PN) inoculated young and old mice. We also measured survival of these immunized mice after aerosol exposure to Streptococcus pneumoniae. As predicted antibody response to TT, but not PN, was significantly reduced in the old animals and T alpha 1 augmented antitetanus antibody in both young and old mice. T alpha 1 did not have an effect on anti pneumococcal antibody production. All mice that had received PN did have an antibody response, yet survival after exposure to the organism was strikingly less in the old animals. Our data support the contention that antibody response to T-dependent antigens (such as tetanus toxoid) falls with aging but can be reconstituted somewhat by thymic factors. Furthermore, for T-independent antigen (such as pneumococcal capsular antigens) the age-related changes are less evident. In the latter situation, the presence of a brisk antibody response after vaccination was not sufficient to prevent pneumonia and death in old animals.
