Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A Phase I clinical trial of N-(phosphonacetyl)-L-aspartate, an antimetabolite which inhibits a key enzyme in the de novo pathway of pyrimidine biosynthesis, was conducted. N-(Phosphonacetyl)-L-aspartate was given as an i.v. 15-min infusion once daily for five days; cycles of treatment were repeated every three weeks. Thirty-four patients received treatment. Dose-limiting toxicity was observed at 1500 to 2000 mg/sq m/day and was manifested by skin rash, diarrhea, and stomatitis. Rash and diarrhea usually began during the first week of treatment and persisted up to Day 17 of a cycle of therapy. No consistent hematopoietic, hepatic, or renal toxicity was observed. One partial response in a patient with colon carcinoma was seen and continues at more than eight months. Stable disease was observed in three patients with colon carcinoma, two patients with hypernephroma, one patient with pancreatic carcinoma, and one patient with melanoma. The predictability and reversibility of toxicity and the suggestion of antitumor activity in humans are observations which support the further evaluation of N-(phosphonacetyl)-L-aspartate in Phase II studies.
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PMID:Phase I trial of N-(phosphonacetyl)-L-aspartate. 15 1

Maytansine, a new ansa macrolide antitumor antibiotic, was administered to 60 patients as part of a phase I study. The doses given ranged from 0.01 (starting level) to 0.9 mg/m2 for 3 days. The toxic effects encountered consisted principally of nausea, vomiting, diarrhea, and occasionally, stomatitis and alopecia. Superficial phlebitis was also encountered and occurred when the drug was diluted in a volume of less than 250 ml. Myelosuppression occurred infrequently; it was almost regularly associated with abnormal liver function tests. Antitumor activity was detected in one patient each with melanoma, breast carcinoma; and head and neck clear cell carcinoma. Further studies are indicated with this compound since it has shown evidence of activity with little or no myelosuppression.
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PMID:Phase I study of maytansine using a 3-day schedule. 34 10

Twenty-six patients with disseminated malignant melanoma were treated with intermittent bolus DTIC and actinomycin D in an escalating dose schedule, starting at 650 and 1 mg/m2 respectively. Courses were repeated at 3--4-week intervals. Twenty four patients were evaluable for toxicity and 22 were evaluable for response. Two patients (9%) had a complete remission lasting 7+ and 14 months, and three patients (14%) had a partial remission lasting 2+, 5+, and 14+ months. Nausea and vomiting, lasting 24 hours, was observed in 88% of patients, while diarrhea was noted in 17%. Stomatitis and alopecia were less frequently observed. All responses occurred at nonmyelosuppressive doses and in patients with visceral-predominant metastases. This schedule offers the patient the convenience of single-day treatment and less prolonged gastrointestinal intolerance. Further evaluation of this drug combination and schedule would appear to be indicated.
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PMID:Phase I--II study of intermittent bolus administration of DTIC and actinomycin D in metastatic malignant melanoma. 35 80

During the phase I study of maytansine at our institution, some activity was observed against breast carcinoma and melanoma. A phase II study was thus initiated to more thoroughly investigate the activity of this drug against these two tumors. In 33 evaluable patients with melanoma, no complete or partial responses were observed. Twenty-one evaluable patients with breast cancer were entered and only one response (partial) was seen. The toxicity was similar to that observed in the phase I study and consisted mainly of diarrhea, paresthesias, phlebitis, and flu-like symptoms. Myelosuppression was infrequent and was short-lived when it occurred.
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PMID:Results of a phase II study of maytansine in patients with breast carcinoma and melanoma. 37 3

ImuVert, a new biological response modifier, was evaluated for toxicity and potential efficacy in patients with advanced cancer. This agent consists of sized, labile, natural membrane vesicles associated with ribosomes derived from Serratia marcescens. ImuVert induces enhanced in vitro macrophage and natural-killer-cell-mediated cytotoxicity, and has demonstrated antitumor activity in palpable animal tumor systems. A group of 39 patients with a variety of tumors, 25 men, 14 women, with a mean performance status (Karnofsky) of 80% and median age of 57 years were entered into this trial. ImuVert was administered subcutaneously weekly for a minimum of 3 weeks. A total of 183 treatments were evaluated. Flu-like systemic toxicities, including fever, chills, nausea, vomiting, diarrhea and hypotension were observed. Erythema, induration and tenderness developed at the injection sites. Myelosuppression, thrombocytopenia, anaphylaxis, rental and hepatic toxicities did not occur. All symptoms resolved within 24 h. Two patients with nodular lymphoma achieved a partial response and two minor responses were seen in patients with glioblastoma and melanoma. On the basis of ImuVert's biological activity, and tolerable toxicity it warrants further clinical investigation.
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PMID:Phase I trial of ImuVert (natural membrane vesicles associated with ribosomes) in patients with advanced cancer. 139 37

Rhizoxin is a 16-membered antifungal macrocyclic lactone isolated from the plant pathogenic fungus Rhizopus chinensis. The compound binds to tubulin, preventing microtubule formation, and inhibiting mitosis. It possesses antitumour activity in vivo against various preclinical murine models, both leukaemias and solid tumours model, as well as in vincristine- and doxorubicin-resistant leukaemia lines. In the present study, cytotoxic activity was observed in human tumour cell lines in vitro at very low concentrations (+/- 10(-10) M) particularly against melanoma, colon, renal, non-small cell and small cell lung cancer. In vivo antitumour activity was demonstrated in murine P388 and L1210 murine leukaemias, solid tumour models B16 melanoma and M5076 sarcoma, and in 5 out of 9 human solid tumour xenografts: LOX melanoma, MX-1 breast cancer, non-small cell lung cancer A549, and small cell lung cancers LXFS 605 and LXFS 650. The absence of cross-resistance to vinca alkaloids was confirmed in vivo against the vincristine-resistant P388 leukaemia subline and the vincristine-resistant human small cell lung cancer LXFS 650. In addition, the antitumour activity of rhizoxin was improved by prolonged or repeated drug administration indicating a schedule dependency. In animal toxicology studies, transient changes in erythrocyte and leukocyte numbers, local phlebitis, diarrhea, and spermatogenic arrest were observed. The LD10 value of rhizoxin after a single intravenous injection was 2.8 mg/kg (8.4 mg/m2). One-tenth of the mouse equivalent LD10 (0.84 mg/m2), the starting dose for clinical phase I studies, was considered to be safe in rats.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Preclinical antitumour activity and animal toxicology studies of rhizoxin, a novel tubulin-interacting agent. 145 59

Thirty-seven patients with advanced malignancies were treated sequentially with recombinant interferon-gamma (rIFN-gamma) and recombinant interleukin-2 (rIL-2) in an outpatient dose escalation clinical trial. rIFN-gamma (0.1 or 0.25 mg/m2/day) was administered by intramuscular injection, days 1-7 and rIL-2 (12, 18, or 24 x 10(6) IU/m2/day) was administered by a 15-min intravenous bolus, days 8-12. Common toxicities encountered included fever, chills, fatigue, neutropenia, and elevations of SGOT, bilirubin, or creatinine. Hypotension and cardiac and pulmonary toxicities were rare. With repeated cycles of therapy, nausea/vomiting and diarrhea associated with the administration of rIL-2 were seen in greater frequency. There were no treatment-related deaths, and no patient required intensive care unit admission for toxicity management. A complete response was observed in one of 11 patients with renal cancer and a partial response was observed in one of seven patients with malignant melanoma. Due to problems with drug supply, further dose escalation could not be continued, and maximum tolerated doses (MTD) were not determined by strict criteria. However, the combination of rIFN-gamma, 0.25 mg/m2/day, and rIL-2, 24 x 10(6) IU/m2/day, appeared to be beyond the MTD, as three of six patients at this dose level could not complete one cycle of therapy due to toxicity. It is unlikely that higher doses of either agent would be tolerated, and for further study using this schedule, we recommend the doses: rIFN-gamma, 0.1 mg/m2/day, and rIL-2, 24 x 10(6) IU/m2/day.
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PMID:A Southwest Oncology Group Phase I study of the sequential combination of recombinant interferon-gamma and recombinant interleukin-2 in patients with cancer. 151 22

Bryostatin 1, a potent activator of protein kinase C, has antitumor activity against murine lymphoma, leukemia, and melanoma. In vitro, this compound stimulates the release of gamma-interferon, interleukins, and hematopoietic growth factors from accessory cells and activates both T- and B-cells. Bryostatin 1 is also able to stimulate neutrophils to undergo oxidative burst and degranulation. Because of the ability of this compound to stimulate the immune system, cause release of immune mediators, and activate neutrophils, we have examined its effect on bacterial infection by using the gram-negative bacterium Salmonella typhimurium in mice. We find that animals given injections i.v. of S. typhimurium have a shortened life span if they are also given injections i.p. of nonlethal doses of bryostatin 1. There is a dose-response relationship with 100 micrograms/kg bryostatin 1 having a greater effect on survival than 40 micrograms/kg. Below 40 micrograms/kg there are no effects on survival. Analysis of the first 4 h of Salmonella infection demonstrates that bryostatin 1 does not affect the blood clearance of the bacterium. However, by day 2 of infection greater numbers of bacteria are found in the livers and spleens of mice given injections of bryostatin 1. By day 5, 10-fold more S. typhimurium bacteria are found in the livers and spleens of mice receiving 40 micrograms/kg of bryostatin 1. To determine whether bryostatin 1 was affecting growth or causing the death of bacteria, we used a Salmonella carrying a plasmid which has a temperature-sensitive origin of replication and is unable to replicate when the bacteria are in mice. This experiment demonstrates that bryostatin 1 represses bacterial killing but does not affect bacterial growth. Bryostatin 1 given i.p. stimulates a transient syndrome of weight loss and diarrhea from which the mice recover and regain weight, suggesting that bryostatin 1 may release a number of important humoral mediators in vivo. The weight loss is exacerbated by Salmonella infection with mice receiving bryostatin 1 and S. typhimurium, in that they lose approximately 33% of body weight prior to death. Thus, at doses used to treat murine tumors, bryostatin 1 treatment does not affect the clearance of S. typhimurium from the blood but does decrease the killing of bacteria in the liver and spleen, leading to early animal death. Such potential effects of bryostatin 1 on the outcome of bacterial infections should be evaluated in ongoing human trials of this agent.
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PMID:In vivo administration of bryostatin 1, a protein kinase C activator, decreases murine resistance to Salmonella typhimurium. 155 18

We conducted a phase I study of low-dose cyclophosphamide and recombinant interleukin-2 (rIL-2) in 66 patients with advanced cancer resistant to standard therapy. All patients were evaluable for toxicity and 46 patients were evaluable for antitumor response. Patients evaluable for antitumor response included 23 with malignant melanoma, 10 with renal cell carcinoma, 4 with colon cancer, and 9 with various other solid tumors. All patients received i.v. cyclophosphamide (350 mg/m2) on day 1 followed by rIL-2 via 15 min i.v. infusion on days 4-8 and 11-15. The doses of rIL-2 ranged from 6.0 to 36.0 x 10(6) IU/m2. Each treatment cycle consisted of 21 days and a total of 113 cycles was administered. The number of treatment cycles administered per patient ranged from 1 to 8. The dose-limiting toxicities associated with rIL-2 included altered mental status, arthralgias, diarrhea, fatigue, fever, hypotension, nausea/vomiting, and peripheral edema. Twelve patients (18%) were removed from the study secondary to toxicity. Among the evaluable patients, 2 (4%) (malignant melanoma, renal cell carcinoma) developed a partial remission, 13 (29%) maintained stable disease, and 31 (67%) developed progressive disease. We conclude that the combination of low-dose cyclophosphamide and rIL-2 is tolerable in most patients but our data do not suggest an improved response rate for the combination vs. rIL-2 alone.
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PMID:Phase I study of low-dose cyclophosphamide and recombinant interleukin-2 for the treatment of advanced cancer. 159 14

Untreated and minimally pretreated solid tumor patients received alternating sequences of taxol and cisplatin. Sequential dose escalation of each agent using taxol doses of 110 or 135 mg/m2 and cisplatin doses of 50 or 75 mg/m2 resulted in four dosage permutations that induced grades 3 and 4 neutropenia in 72% to 84% and 50% to 53% of courses, respectively. Neutropenia was brief, and hospitalization for neutropenia and fever was required in 13% to 24% of courses. However, further escalation of taxol to 170 or 200 mg/m2 induced grade 4 neutropenia in 79% to 82% of courses. At the highest taxol-cisplatin dose level (200 mg/m2 to 75 mg/m2), the mean neutrophil count nadir was 98/microL, and hospitalization for neutropenia and fever was required in 64% of courses. The sequence of cisplatin before taxol, which has less antitumor activity in vitro, induced more profound neutropenia than the alternate sequence. Pharmacologic studies indicated that this difference was probably due to 25% lower taxol clearance rates when cisplatin preceded taxol. Although neurotoxicity was initially thought to be a potentially serious effect of the combination, mild to modest neurotoxicity occurred in only 27% of patients. Adverse effects also included myalgias, alopecia, vomiting, diarrhea, bradycardia, and asymptomatic ventricular tachycardia. Objective responses were noted in melanoma, as well as non-small-cell lung, ovarian, breast, head and neck, colon, and pancreatic carcinomas. Based on these results, the sequence of taxol before cisplatin at doses of 135 and 75 mg/m2, respectively, is recommended for phase II/III trials, with escalation of taxol to 170 mg/m2 if treatment is well tolerated.
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PMID:Sequences of taxol and cisplatin: a phase I and pharmacologic study. 167 80


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