Biomedical subjects

J Carmichael

Publications and source records attributed to J Carmichael.

At least 73 records · Page 4Linked to original sources

PubMed1997

Topotecan versus paclitaxel for the treatment of recurrent epithelial ovarian cancer.

PURPOSE: Topotecan and paclitaxel were evaluated in a randomized, multicenter study of patients with advanced epithelial ovarian carcinoma who had progressed during or after one platinum-based regimen. PATIENTS AND METHODS: Patients received either topotecan (1.5 mg/m2) as a 30-minute infusion daily for 5 days every 21 days (n = 112) or paclitaxel (175 mg/m2) infused over 3 hours every 21 days (n = 114). Patients had bidimensionally measurable disease and were assessed for efficacy and toxicity. RESULTS: Response rate was 23 of 112 (20.5%) in topotecan-treated patients and 15 of 114 (13.2%) in paclitaxel-treated patients (P = .138). Disease stabilization for at least 8 weeks was noted in 30% of patients with topotecan and 33% of patients with paclitaxel. Median durations of response to topotecan and paclitaxel were 32 and 20 weeks, respectively (P = .222) and median times to progression were 23 and 14 weeks, respectively (P = .002). Median survival was 61 weeks for topotecan and 43 weeks for paclitaxel (P = .515). Response rates for topotecan and paclitaxel were 13.3% versus 6.7% (P = .303) in resistant patients (not responded to prior platinum-based therapy or progressed within 6 months of an initial response) and 28.8% versus 20.0% (P = .213) in sensitive patients (progressed > 6 months after response). Neutropenia was significantly more frequent on the topotecan arm 79% versus paclitaxel arm 23% (P < .01). It was short-lasting and noncumulative in both arms. Nonhematologic toxicities were generally mild (grades 1 to 2) for both agents. CONCLUSION: Topotecan has efficacy at least equivalent to paclitaxel manifested by the higher response rate and significantly longer time to progression.

Adult↗

PubMed1997

Topotecan, an active new antineoplastic agent: review and current status.

Topotecan (Hycamtin) is a water soluble semisynthetic analogue of the alkaloid camptothecin which has antitumour activity in preclinical models in vitro and in vivo. A range of Phase I studies has been performed and a daily x 5 iv. schedule, which showed most promising evidence of activity, was selected for extensive clinical evaluation. To date, topotecan has been shown to be active in a number of malignancies, including metastatic ovarian cancer, recurrent small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), breast cancer, colorectal cancer and myelodysplastic syndrome. In ovarian cancer, response rates of around 15% were identified in patients who had failed standard chemotherapy, and in a randomised, comparative study with paclitaxel response rates of 20% (topotecan) and 13% (paclitaxel) were observed. In addition, overall time to progression was impressive at 23 weeks (topotecan) compared with 14 weeks (paclitaxel). In recurrent SCLC, topotecan has shown good activity in sensitive patients with a response rate of 39%, although the response rate in refractory patients was considerably lower (7%). Median survival of all patients was 5.4 months, acceptable for this difficult clinical scenario. Topotecan is well-tolerated in the majority of patients and subjective toxicities are uncommon. The principal side-effect is myelosuppression, mainly neutropenia. Serious clinical sequelae are relatively uncommon and non-cumulative. Nonhaematological toxicities are generally mild and not dose-limiting. In clinical use, topotecan has exhibited activity in multiple tumour types, with a side-effect profile that is predictable and manageable. The drug is under evaluation in other tumour types and in combination chemotherapy regimens.

Journal Article↗

PubMed1997

Efficacy and safety of topotecan in the treatment of advanced ovarian carcinoma.

Topotecan (Hycamtin; SmithKline Beecham Pharmaceuticals, Philadelphia, PA) has emerged as a promising new chemotherapy drug for patients with refractory and progressive stage III and IV epithelial ovarian carcinoma. A semisynthetic analog of camptothecin, topotecan exerts its antitumor effects through inhibition of the nuclear enzyme topoisomerase I. Phase I trials found antitumor activity in many topotecan dosing schedules, one of which involved the administration of topotecan daily as a 30-minute infusion for 5 consecutive days, with the cycle repeated every 21 days. With this schedule, the maximum tolerated dose was found to be 1.5 mg/m2/d. In a series of phase II investigations in platinum-resistant ovarian cancer patients, response rates have ranged from 13% to 25%. In addition, a number of patients exhibit prolonged disease stabilization, with overall rates of nonprogression ranging from 37% to 81%. Activity in paclitaxel-resistant patients is also seen, with a multicenter phase II trial showing a response rate of 13% among first-line paclitaxel failures and 14.3% among second-line failures. A phase III trial compared topotecan and paclitaxel as second-line therapies in 226 advanced ovarian cancer patients who had been previously treated with platinum-containing regimens. Preliminary data show that patients treated with topotecan evidenced a higher response rate (23% v 14%), longer response duration (32 weeks v 20 weeks), and significantly longer time to progression (23 weeks v 14 weeks; P = .002). Additional schedules are still being evaluated, with a phase II trial of prolonged infusion of relatively low-dose topotecan over 21 days demonstrating a 37% response rate in 16 patients. All phase II and III trials analyzed thus far indicate that topotecan is well tolerated with an acceptable toxicity profile, with myelosuppression as the dose-limiting toxicity. Hematologic toxicities are predictable, of short duration, and noncumulative. Mild to moderate nonhematologic toxicities are manageable. These findings demonstrate that topotecan is a viable new second-line or salvage treatment for patients with advanced ovarian cancer who are refractory or resistant to prior chemotherapy, including platinum-based agents and/or paclitaxel.

Antineoplastic Agents↗

PubMed1997

UFT plus leucovorin vs 5-FU plus leucovorin for metastatic colorectal cancer.

An open-label, randomized phase III trial has been established to compare the efficacy and safety profile of tegafur and uracil (UFT) plus leucovorin with fluorouracil (5-FU) plus leucovorin as first-line chemotherapy for patients with metastatic colorectal adenocarcinoma. The primary end point of this study is time to progression. Secondary end points include tumor response, symptom control, quality of life, and pharmacoeconomics. Patients randomized to the experimental arm will receive UFT 300 mg/m2/day for 28 days followed by 1 week of rest, plus leucovorin 30 mg three times daily for 28 days. Patients in the control arm will receive 5-FU 425 mg/m2/day plus leucovorin 20 mg/m2/day for 5 days every 35 days. All patients eligible to participate in the study have evaluable or measurable disease. Assessments of tumor size and symptoms will be conducted every 5 weeks (every cycle), with scanning investigations repeated every 10 weeks (two cycles). Symptom evaluation includes assessment of pain, analgesic use, weight loss, and performance status. The intention was to recruit 362 patients by April 1996, with accrual planned for completion by July 1997. As of May 1997, 312 patients had been randomized in 15 countries, covering 45 active sites. All patients had good performance status, and the majority had no prior adjuvant chemotherapy. The study is currently ongoing, and no safety data are available at this time.

Adult↗

PubMed1997

A phase II trial of epirubicin plus paclitaxel in metastatic breast cancer. United Kingdom Coordinating Committee for Cancer Research Breast Cancer Sub-Committee.

Epirubicin and paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is an active combination for the treatment of metastatic breast cancer. A multicenter pilot phase II trial evaluated this combination in 35 patients treated with epirubicin 75 mg/m2 given as a 1-hour infusion, immediately followed by paclitaxel 200 mg/m2 given as a 3-hour infusion every 3 weeks. All patients had metastatic disease and had received a maximum of one chemotherapy regimen for advanced disease. A 43% response rate was observed in 30 evaluable patients, with two complete responses (7%) and 11 partial responses (37%). All patients were evaluable for toxicity. Hematologic toxicity was common and dose limiting. All patients underwent blood counts three times weekly. Grade 4 neutropenia was extremely common (91%), occurring at approximately days 10 to 12 and resolving rapidly in most cases. Thrombocytopenia was rare. Dose reductions were necessary in 10 patients, primarily for myelosuppression, but due to neuropathy in two patients. Alopecia was universal. Cardiac function was measured in all patients every two cycles. Among the first 24 evaluable patients, left ventricular ejection fraction decreased to below 40% in three patients, all of whom had received prior anthracyclines. Treatment was discontinued in one patient, who experienced no further deterioration. Under the auspices of the United Kingdom Coordinating Committee for Cancer Research, a randomized phase III study has been initiated in the United Kingdom to compare this combination of epirubicin/paclitaxel with combination epirubicin/cyclophosphamide. The primary end point of this study is progression-free survival, and the intention is to recruit 350 to 700 patients over the next 2 years.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1996

Radiation biology of lung cancer.

The enormous problem that is lung cancer still defies satisfactory therapeutic strategy. This article summarizes some of the more important laboratory efforts directed at understanding the biology of this complex disease. The radiation sensitivities of established lung cancer cell lines are outlined. The effect of radiation dose rate and chemotherapy is explored. The emerging biology of oncogenetic alterations is explored as it relates to radiation sensitivity in general, and lung cancer in particular. Finally, novel therapeutic approaches including photodynamic therapy are introduced.

Antineoplastic Agents↗

PubMed1996

Phase II study of gemcitabine in patients with advanced pancreatic cancer.

The efficacy and safety of gemcitabine at a starting dose of 800 mg m2 administered once a week for 3 weeks with 1 week's rest was investigated in chemonaive patients with advanced and/or metastatic pancreatic cancer. Of 34 patients, 32 were evaluable for efficacy, 20 patients had metastatic stage IV disease, 25 had a performance status of 1 and 26 (76%) patients has significant pain on presentation. All responses were independently validated by an external oncology review board: two patients achieved a partial response that lasted 5.8 and 5.2 months (6.3%) and six patients were stable for at least 4 weeks. The median duration of survival for evaluable patients was 6.3 months (range 1.6-19.2 months). The tumour markers, CEA, CA 19-9 and CA 195 were serially measured in 16 patients. There was a good correlation with tumour response when all three markers were significantly decreased. In 4 of 16 patients, tumour marker levels decreased by > or = 60%, including the two responders, one patient who survived for 12 months and one patient who showed objective tumour shrinkage but was deemed ineligible for response evaluation because the disease was considered not to be bidimensionally measurable. Symptomatic benefits included improvement in performance status (17.2%), analgesic requirement (7.4%), pain score (28.6%) and nausea (27.3%). The mean number of cycles administered was 2.5 and the mean dosage received was 890 mg m2 per injection. Seventy-four per cent of dose administrations were given on schedule. Toxicity, particularly haematological toxicity, reported as the maximum WHO grade experienced by patients was mild. Infective episodes were rare and limited to WHO grade 2 (6.7%). Nausea and vomiting was generally modest (WHO grade 3, 26.7%). Other side-effects included mild transient flu-like symptoms (seven patients) and peripheral oedema (three patients), which was not associated with abnormal cardiac hepatic or renal function. Gemcitabine has modest activity in pancreatic cancer, a limited positive improvement on a range of patient benefit parameters and has a mild toxicity profile. For these reasons and because of its novel mode of action, gemcitabine warrants further investigation in combination studies in pancreatic cancer.

Adult↗

PubMed1996

A phase I study of gemcitabine and carboplatin in non-small cell lung cancer.

Gemcitabine has shown phase II activity against a range of solid tumor malignancies. This study evaluated a combination of gemcitabine and carboplatin in a phase I trial in 13 chemotherapy-naive patients with non-small cell lung cancer to determine the maximum tolerated dose of carboplatin in combination with gemcitabine. Gemcitabine at a dose of 1,000 mg/m2 was administered on days 1, 8, and 15 of a 28-day cycle and carboplatin was given as a 30. minute infusion immediately before gemcitabine on day 1. Carboplatin dosing was escalated and determined using the Calvert formula, and three patients were treated at the initial predicted dose of area under the curve (AUC) 4 mg/mL/min. Subsequently the carboplatin dose was escalated to a predicted AUC 5.2 mg/mL/min. Pharmacokinetic studies were performed measuring gemcitabine and carboplatin (total platinum) concentrations. Responses were assessed following two cycles of treatment and patients with stable disease or objective responses proceeded to receive a maximum of six cycles. Dose-limiting myelosuppression was identified at a predicted carboplatin AUC 5.2 mg/mL/min, with two patients developing grade 4 neutropenia and two patients grade 4 thrombocytopenia. However, these grade 4 toxicities were not associated with any serious sequelae. In this preliminary study, four partial responses were observed and the median length of survival for all patients was 45 weeks. Pharmacokinetic parameters for gemcitabine were similar to those in patients receiving 1,000 mg/m2 as a single agent, and for carboplatin showed that the delivered dose was slightly below the calculated dose. There was one treatment-related death due to cerebral edema. The combination was well tolerated by the majority of patients, and symptomatic toxicity was similar to single-agent gemcitabine. The combination of gemcitabine and carboplatin is well tolerated in patients with non-small cell lung cancer, with myelosuppression being the dose-limiting toxicity. Symptomatic toxicities were rare and outpatient treatment was easy. In view of the antitumor activity observed, further examination of this combination is warranted. In the first instance, alternate sequencing of the combination with gemcitabine followed by carboplatin is planned in an extended phase I study prior to phase II evaluation.

Adult↗

PubMed1996

Phase II activity of gemcitabine in advanced breast cancer.

Two phase II breast cancer studies have been completed with gemcitabine in patients with locally advanced or metastatic breast cancer. Gemcitabine was administered as a 30 minute intravenous infusion on days 1, 8, and 15 of a 28-day cycle. In a European study of 44 patients, 40 patients were evaluable for response, 26 having received chemotherapy (seven in the adjuvant setting). The mean number of completed cycles administered was 2.7 and 81% of doses were delivered as scheduled. There were three complete responses and seven partial responses, giving an overall response rate of 25.0% (95% confidence interval, 12.7% to 41.2%). Four patients were not evaluable for efficacy: one had insufficient therapy, two had no bidimensionally measurable disease, and one had insufficient therapy and no bidimensionally measurable disease. The median duration of survival was 11.5 months. Hematologic toxicity was generally mild, with World Health Organization grade 3 and 4 leukopenia occurring in 6.8% and 2.3% of patients and neutropenia in 23.0% and 7.0% of patients, respectively. Nonhematologic toxicity was minimal. Flu-like symptoms were mild and transient. Only one patient developed alopecia. In a US study, 18 of 21 heavily pretreated patients were evaluable, all of whom had stage IV disease. The median number of cycles administered was two, with 12% of injections omitted and 31% reduced by 50%. No responses were observed in this smaller study. The safety profile was similar to that in the European study, although myelosuppression was greater in the US study, in which patients were heavily pretreated. The differing results observed from single-agent studies of gemcitabine in advanced breast cancer may be explained in part by the amount of prior chemotherapy received and the lower mean dose of chemotherapy administered in the US study. Responses have been observed in both chemotherapy-naive and previously treated patients. The drug was extremely well tolerated in both studies, even in heavily pretreated patients. In view of its modest toxicity profile and its novel mechanism of action, gemcitabine deserves further evaluation in breast cancer patients and, in particular, because of its relative lack of myelotoxicity would be an ideal candidate for combination chemotherapy.

Adolescent↗

PubMed1995

An open study to assess the safety, tolerance and pharmacokinetics of an intravenous infusion of granisetron given at 3 mg over 30 s in patients receiving chemotherapy for malignant disease.

Granisetron is a highly potent and selective 5-hydroxytryptamine3 (5-HT3) receptor antagonist indicated for the prevention of cytotoxic-induced nausea and vomiting. Clinical trials have demonstrated granisetron to be effective and well tolerated at a standard dose of 40 micrograms/kg or 3 mg given i.v. as a 5-min infusion. In this study, the efficacy and safety of granisetron given as a 30-s infusion was assessed. A total of 21 patients, scheduled to undergo chemotherapy, received a single 3-mg i.v. dose of granisetron over 30 s, completed at 1 h before chemotherapy administration. Patients were allowed two further i.v. doses of granisetron at 3 mg within the 24-h assessment period. Changes from baseline values in vital signs were analysed prior to granisetron administration and at 30 s as well as 1, 10, 15, 30 and 60 min after granisetron administration. Holter ECG recordings were taken for 6 h prior to and 1 h after administration. No significant change was found in vital signs at 30 s or 1 min after granisetron infusion. There was a small but statistically significant fall in diastolic blood pressure as compared with baseline and a non-significant trend in favour of a reduction in heart rate at 10 and 15 min. No ECG abnormality was recorded post-infusion that had not been present pre-infusion. None of these changes was considered to be clinically relevant. The treatment was well tolerated. The most frequently reported adverse events were constipation (n = 6) and headache (n = 5). Maximal plasma levels of granisetron were within the range of 44.57-410 ng/ml except in one patient. The median values recorded for peak concentration (Cmax) and area under the curve (AUC) were 195 ng/ml and 71.2 ng h ml-1, respectively. In conclusion, granisetron at 3 mg was shown to be safe and well tolerated when given as a 30-s i.v. infusion to patients receiving chemotherapy for malignant disease.

Adult↗

PubMed1995

Relationship between expression of topoisomerase II isoforms and intrinsic sensitivity to topoisomerase II inhibitors in breast cancer cell lines.

Topoisomerase II is a key target for many anti-cancer drugs used to treat breast cancer. In human cells there are two closely related, but differentially expressed, topoisomerase II isoforms, designated topoisomerase II alpha and beta. Here, we report the production of a new polyclonal antibody raised against a fragment of the C-terminal domain of the 180 kDa form of topoisomerase II (the beta isoform), which does not cross-react with the 170 kDa form (the alpha isoform). Using this antibody, together with a polyclonal antibody specific for the 170 kDa isoform of topoisomerase II, we have examined the relationship between the sensitivity of a panel of human breast cancer cell lines to different classes of topoisomerase II inhibitors and cellular levels of the topoisomerase II alpha and beta proteins. We found that sensitivity to amsacrine showed a correlation with the level of expression of topoisomerase II alpha protein, and that sensitivity to etoposide showed a similar correlation with the level of expression of topoisomerase II beta protein. There was also a relationship between sensitivity of these cell lines to mitoxantrone and the cellular level of both isoforms of topoisomerase II. No relationship was found between the level of mRNA for topoisomerase II alpha or beta, and either sensitivity of breast cancer cell lines to topoisomerase II inhibitors or the level of topoisomerase II protein expression.

Antibody Specificity↗

PubMed1995

Advanced breast cancer: a phase II trial with gemcitabine.

PURPOSE: In this phase II study, the efficacy and tolerability of gemcitabine were studied in 44 patients with locally advanced or metastatic breast cancer. PATIENTS AND METHODS: Of 40 patients assessable for response, 14 were chemotherapy-naive, seven had received adjuvant chemotherapy, and 19 had received one prior chemotherapy regimen for metastatic disease. Gemcitabine was administered as a 30-minute intravenous infusion once a week for 3 weeks followed by a 1-week rest every 4 weeks. The mean number of completed cycles administered was 2.7 and the mean dosage delivered was 725 mg/m2 per injection. Eighty-one percent of doses were delivered as scheduled. RESULTS: There were three complete responses and seven partial responses, for an overall response rate of 25.0% (95% confidence interval [CI], 12.7% to 41.2%). Four patients were not assessable for efficacy (one had insufficient therapy, two had no bidimensionally measurable disease, and one had neither). All responses were independently validated by an external oncology review board. Responses were observed early in treatment, with a median time to response of 1.9 months. The median survival duration for all 40 assessable patients was 11.5 months. Hematologic toxicity was generally mild, with World Health Organization (WHO) grade 3 and 4 leukopenia occurring in 6.8% and 2.3% of patients and neutropenia in 23.3% and 7.0%, of patients, respectively. The only other grade 4 toxicities were infection and nausea and vomiting in one patient each. One patient was withdrawn due to shortness of breath, possibly drug-related. Flu-like symptoms, which were mild, transient, and treatable with acetominophen, were reported in 6.8% of patients. Only one patient developed alopecia of severity greater than WHO grade 2. CONCLUSION: In view of the single-agent activity seen in advanced breast cancer, modest toxicity profile, and novel mechanism of action, gemcitabine deserves evaluation in breast cancer and is an ideal candidate for combination therapy.

Adult↗

PubMed1994

Reversal of P-glycoprotein-mediated multidrug resistance by pure anti-oestrogens and novel tamoxifen derivatives.

In this study the ability of five novel anti-oestrogens [4-iodotamoxifen, pyrrolidino-4-iodotamoxifen, ethyl bromide tamoxifen (EBTx), ICI 164,384 (ICI 164) and ICI 182,780] to alter drug toxicity to multidrug resistant cell lines have been compared. The effect of these compounds on ATP-dependent vinblastine (VBL) transport was also tested using inside-out vesicles (IOV) prepared from highly P-glycoprotein (Pgp)-expressing CCRF-CEM/VBL1000 cells. The pure anti-oestrogen ICI 164 was most effective, enhancing doxorubicin and VBL toxicity to MCF-7Adr cells 25- and 35-fold, respectively, and was also the best inhibitor of ATP-dependent [3H]VBL accumulation by IOV. Pure anti-oestrogens, tamoxifen and iodotamoxifens completely reversed VBL resistance in the mdr1 transfected lung cancer cell line, S1/1.1, where resistance relative to wild-type cells was mediated solely by Pgp. The membrane impermeant tamoxifen derivative EBTx did not modify drug resistance, yet was as effective an inhibitor of VBL accumulation by inside-out Pgp-positive vesicles as tamoxifen. This indicates an intracellular role for tamoxifen and its derivatives in the modulation of Pgp-mediated drug resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1994

Expression of xenobiotic-metabolizing enzymes by primary and secondary hepatic tumors in man.

PURPOSE: To determine the immunohistochemical expression of xenobiotic-metabolising enzymes (XME) in normal livers, primary hepatocellular carcinomas (hepatomas) and secondary hepatic tumors from colonic primary tumors. METHODS AND MATERIALS: The expression of XME in primary (n = 16) and secondary (n = 21) hepatic tumors and patients with no malignancies (n = 20) were investigated using polyclonal antibodies raised against the following rat enzymes CYP1A1, CYP2B1, CYP2C6, CYP3A1, CYP4A1, cytochrome P-450 reductase, epoxide hydrolase and testosterone UDP-glucuronyl transferase. The rat cytochrome P-450 antibodies recognize various human isoenzymes within the same gene family. Immunohistochemistry was undertaken using the immunoperoxidase and alkaline phosphatase anti-alkaline phosphatase techniques. RESULTS: There was a reduction in the overall expression of all XME by tumor tissue compared to adjacent nonneoplastic liver cells (p = 0.008), more in livers with secondary tumors (p < 0.0001) and reduced expression of XME by hepatomas and secondary liver tumors compared to livers with no malignancy. A tendency for higher expression of all XME by nonneoplastic liver cells from patients with hepatomas relative to nonmalignant livers was observed, with significantly higher expression of CYP3A4/5 and testosterone UDP-GT enzymes (odds ratio 3.12; CI 1.59-6.10). CONCLUSION: The expression of XME by tumor tissue is reduced in primary and secondary hepatic malignancies. The expression of XME by nonneoplastic liver cells is higher in patients with hepatomas than patients with no hepatic malignancies. These alterations in XME activities may have important therapeutic implications in the response and toxicity to systemic anti-cancer therapy, due to altered pharmacokinetics. In addition, differential expression of these enzymes by normal and malignant cells may be important for the rational design of selective anti-tumor drugs.

Adult↗

PubMed1994

The role of DT-diaphorase in determining the sensitivity of human tumor cells to tirapazamine (SR 4233).

PURPOSE: To determine the dependency of the aerobic and hypoxic toxicity of tirapazamine on the intracellular activity of DT-diaphorase. METHODS AND MATERIALS: A panel of 18 human cell lines comprising predominantly small cell and nonsmall cell lung cancer and breast cancer lines were used. The activity of DT-diaphorase was determined in cytosolic preparations from cell lysates. The toxicity of tirapazamine was determined using the MTT assay after either 96 or 3 h aerobic exposure or 3 h treatment in hypoxia. RESULTS: The cell lines exhibited a 5000-fold range in DT-diaphorase activity. In toxicity experiments, values of IC50 range from 10.2-120 microM and from 155-1230 for 96 and 3 h aerobic exposures, respectively. In N2, IC50s ranged from 8-55 microM. None of the toxicity values correlate with activity of DT-diaphorase, neither did the ratio of aerobic:hypoxic toxicity (differential toxicity). CONCLUSION: The expression of DT-diaphorase in human tumor cells does not affect the toxicity of tirapazamine.

Antineoplastic Agents↗

PubMed1994

Cancer chemotherapy: identifying novel anticancer drugs.

There are now around 60 cytotoxic drugs licensed for use in cancer therapy in the United Kingdom. For certain malignancies such as childhood cancers, haematological malignancies, and germ cell tumours chemotherapy has been pivotal to the substantial improvement in therapeutic outcome achieved over the past 10 years. In contrast, improvements in the systemic management of adult solid tumours have been less dramatic. There is a clear and urgent need for new, more effective drugs for lung, breast, and colorectal malignancies. This paper examines the processes in identifying, developing, and evaluating new drugs with anticancer activity.

Antineoplastic Agents↗

PubMed1994

A phase II study of high-dose hydroxyurea and dacarbazine (DTIC) in the treatment of metastatic malignant melanoma.

Dacarbazine (DTIC) exerts its major biochemical effect through the formation of methylated DNA adducts. Hydroxyurea (HU) is a ribonucleotide reductase inhibitor which blocks DNA excision-repair by the depletion of intracellular ribonucleotides. Combination of HU and DTIC was used to enhance the activity of DTIC by inhibiting DNA repair. 16 patients with metastatic malignant melanoma were treated with the combination. All patients had measurable disease and none had received prior systemic therapy. Hydroxyurea was given as a continuous intravenous (i.v.) infusion of 1 g/h (total 36 g) and DTIC 1 g/m2 i.v. over 1 h, 23 h from the start of hydroxyurea infusion. 4 patients achieved partial remission with an objective remission rate of 25% [95% confidence interval (CI) 7-52%]. Median duration of response was 3.5 months. 3 of the responding patients had predominant visceral metastases. Disease was stabilised in 5 patients with a median time to progression of 16 months. The predominant toxicity to this treatment was gastrointestinal, with 3 patients developing grade 3 nausea/vomiting. Only 1 patient developed grade 3 leucopenia complicated by septicaemia. It is concluded that the combination of hydroxyurea and DTIC is a well-tolerated regimen with activity against visceral metastases from malignant melanoma but the duration of response to this treatment is short.

Adult↗

PubMed1994

Selective toxicity of TGF-alpha-PE40 to EGFR-positive cell lines: selective protection of low EGFR-expressing cell lines by EGF.

The sensitivity of human breast and lung cancer cell lines to TGF-alpha-PE40, a novel chimeric recombinant cytotoxin composed of two independent domains, (i) TGF-alpha and (ii) a 40 kDa segment of the Pseudomonas exotoxin protein, PE-40, was investigated. Toxicity varied widely, correlated with epidermal growth factor receptor (EGFR) levels (P = 0.01) and was greatly reduced by EGF, indicating that binding of TGF-alpha-PE40 to EGFR is important in mediating toxicity. Cell lines expressing low EGFR levels were most highly protected by EGF, indicating that normal (low EGFR-expressing) tissue may be selectively protected by EGF in vivo. P-glycoprotein did not confer resistance to TGF-alpha-PE40, and toxicity was unaffected by multidrug resistance-modulating agents (cyclosporin A, tamoxifen, verapamil), indicating a role for TGF-alpha-PE40 in the clinical management of drug-resistant tumours.

Breast Neoplasms↗