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At least 19 recordsLinked to original sources
PubMed1981

A controlled prospective trial of adjuvant razoxane in resectable colorectal cancer.

Following resection of their tumour, 162 patients with colorectal cancer entered a prospective randomized controlled clinical trial of adjuvant oral razoxane. Thirty-one patients were Duke's group A; 49 group B; 61 group C; and 17 group D; an additional four patients were randomized in error. The adjuvant group received the usual clinical care and 125 mg razoxane twice daily for 5 consecutive days (monday-friday) every week indefinitely. Control patients received the same clinical care as the adjuvant group, but no razoxane. At 3 years, 134 patients (84%) are evaluable. The recurrence rate in the first 6 months was 20% and 28% respectively in the Duke's B and C controls compared with 4% and 9% in the corresponding razoxane treated patients. Most recurrences occurred within the first 6 months from randomization. When all patients as randomized are included in the analysis of survival, irrespective of whether they were cured by surgery (Duke's A), had advanced cancer (Duke's D), or took no razoxane when randomized to take it, then as might be expected any differences there may be between the razoxane-treated and control patients with minimal residual disease (Duke's B and C) are so distorted that the p value of the difference in survival was 0.93. If however only patients with Duke's group B or C are taken (49 controls and 47 treated), log-rank analysis reveals a difference in the cancer mortality curves (p = 0.07). If patients who had been randomized to take razoxane, but who had not taken it at any time (and therefore received the same treatment as controls) are analysed with the controls, the difference between the two groups increases further, with p less than 0.05. The razoxane-treated patients experienced no significant toxicity apart from a readily reversible mild leukopenia in 52% while gastrointestinal symptoms necessitated stopping the drug in only four patients. These four all took the drug for less than 4 weeks. Because there was no toxicity to subtract from any benefit razoxane adjuvant treatment produced and the quality of life was not impaired, the therapeutic benefit of surgery wsa increased to the extent that razoxane increased survival of patients with Duke's B and C tumours.

Clinical Trials as Topic↗
PubMed1984

Inhibition of experimental colorectal cancer by razoxane (ICRF-159).

Large bowel cancer induced in rats by dimethylhydrazine (DMH) closely resembles human disease both histologically and clinically. In this study it has been used to assess the antimitotic drug razoxane (ICRF-159). Dimethylhydrazine induced benign colorectal tumours after 20 weeks and adenocarcinomas from 30 weeks. Razoxane was given from week 25 until the end of experiment (week 35) to see if this drug could inhibit the development of tumours. Animals were randomly allocated to four groups: DMH + razoxane (26), DMH + control (26), control + razoxane (25), control + control (25). There were fewer malignant colorectal tumours in rats receiving razoxane than in the controls (10 vs. 24; P = 0.04). Some animals developed malignant tumours of the small intestine as well as the large bowel and the number of malignant tumours for the whole intestinal tract was also reduced in animals receiving razoxane (15 vs. 32; P = 0.025). This study demonstrates inhibition of the development of malignant tumours in rats by razoxane. This finding may have relevance to colorectal cancer in man where razoxane has been used in disseminated disease and as an adjuvant to surgery.

1,2-Dimethylhydrazine↗
PubMedDate not supplied

Therapeutic efficacy of two different cytostatic-linked phosphonates in combination with razoxane in the transplantable osteosarcoma of the rat.

Two new compounds, 4-[4-[bis-(2-chloroethyl)-amino-]phenyl]-1- hydroxybutane-1,1-bisphosphonic acid (BAD) and aminotris-(methylenephosphonato)-diamminoplatinum(II) (ADP) that both have cytostatic and osteotropic properties, have shown good therapeutic efficacy against an osteosarcoma which metastasizes and kills by lung metastases. We therefore combined each of these drugs with the antimetastic agent razoxane. Razoxane (20 mg/kg i.p., 5 days/week for 6 weeks) was administered in combination with either BAD (30 mg/kg i.p.) or ADP (37.5 mg/kg i.v.) twice weekly for 3 weeks. Tumour volumes, body weight, survival time and occurrence of metastases were recorded, in addition to the measurement of the metastasis area compared to the total lung area in serial histological lung samples. In both experiments, razoxane effected a significant increase in life span while being ineffective in tumour inhibition. Razoxane in combination with BAD displayed an enhanced anticancer activity which was not significant. ADP had a good antineoplastic activity and a large increase in survival time (144 per cent ILS). Razoxane used in combination with ADP did not influence antitumour efficacy. Median survivals of both ADP-treated groups were significantly longer than the razoxane-treated group. Analysis of the lung metastasis area showed a maximum of 57 per cent for the controls while all treated groups occupied a lesser area. The lowest metastases area was found with the combination treatment BAD + RAZ (18 per cent). This was considered an antimetastatic effect, while ADP treatment effected a time delay only. No change in metastatic pattern was observed in any of the treatment groups. Histological examination showed no effect on the capillaries in the proliferating region of the tumours that could account for the lower occurrence of metastases.

Animals↗
PubMed1985

The mutagenic activity of razoxane (ICRF 159): an anticancer agent.

The mutagenic activity of razoxane (ICRF 159) was studied using the Salmonella/microsome assay and rodent bone-marrow micronucleus and metaphase assays. Razoxane (up to 5000 micrograms/plate) did not cause an increase in the mutation frequency in the Salmonella/microsome assay. In the mouse micronucleus assay razoxane (200 and 400 mg kg-1 i.p.) was cytotoxic to the bone marrow cells (which limited the analysis) but an increase in micronucleated polychromatic erythrocytes was observed in razoxane dosed animals (5-fold compared to control value). In the Chinese hamster metaphase assay razoxane (up to 500 mg kg-1 orally) induced abnormal chromosome condensation and an increase in structural chromosome aberrations (7 fold compared to control value) as well as an increase in the number of polypoid cells (8-fold compared to control value). The mutagenic effect of razoxane was restricted to eukaryotic organisms and was associated with specific chromosomal changes.

Animals↗
PubMedDate not supplied

Prospective serial liver ultrasound scanning in resectable colorectal cancer treated with adjuvant razoxane.

Prospective serial ultrasound scanning (U/S) of the liver at 3-monthly intervals has been used to detect the presence of hepatic metastases from successfully resected Dukes' A, B and C grade colorectal carcinomas in a trial of the antimetastatic agent razoxane (ICRF 159). One hundred and twenty-six consecutive patients were randomly allocated to either adjuvant razoxane treatment (61) or to no further treatment (65). Twenty-six patients, 15 in the control group (23 per cent) and 11 in the razoxane treatment group (18 per cent) have developed hepatic metastases. All but three patients in the treated group and four in the controls were detected by U/S. In the control group four patients had definite metastases when metastases were first seen by ultrasound and three more, among the eight who initially had probable metastases, became definite metastases on ultrasound. In the treated group four patients had definite metastases and four more developed them amongst 12 who had probable metastases. The remaining eight of these 12 all regressed completely. This compared with only one complete regression (additionally on 5-FU for lung secondaries) amongst the eight controls who had probable metastases. The median time to development of liver metastases detected by U/S and other means was 59 weeks in the control group and 91 weeks in the razoxane treatment group. Ultrasound has proved to be a safe, sensitive and acceptable serial imaging technique for detecting colorectal liver metastases. Used prospectively, U/S has been valuable in monitoring the natural history of liver metastases and their behaviour during razoxane treatment.

Colonic Neoplasms↗
PubMed1983

The effects of razoxane (ICRF 159) on the production of collagenase and inhibitor (TIMP) by stimulated rabbit articular chondrocytes.

Monolayer cultures of rabbit chondrocytes were stimulated to produce collagenase with conditioned medium from human peripheral blood mononuclear cells (MCM), and the ability of Razoxane to modulate the production of collagenase and specific tissue inhibitor of metalloproteinases (TIMP) was studied. Collagenase production was inhibited and TIMP increased by Razoxane, in a dose-dependent manner, when cells were treated daily for 3 days. Over this period the effect of Razoxane was progressive; 50 micrograms/ml or less had no effect at day 1 but 50 micrograms/ml was effective by day 3. The effectiveness of Razoxane was inversely related to the degree of MCM stimulation and the confluency of the culture. On removal of the drug, chondrocytes stimulated with MCM recovered their ability to produce collagenase, and TIMP production returned to near normal. The results suggest that the ability of Razoxane to reduce collagenase and increase TIMP production may correlate with its effectiveness in treating psoriatic arthritis.

Animals↗
PubMed1982

Interaction of razoxane and radiation on cultured Chinese hamster cells.

Razoxane [(+/-)-1,2-bis(3,5-dioxopiperazine-1-yl)propane] was investigated for its effects on the survival of irradiated Chinese hamster fibroblasts in vitro. Razoxane alone produced cytotoxicity that was dependent upon drug concentration and pulse exposure time, with a preferential lethality for cells treated while in the DNA-synthetic phase. Razoxane enhanced radiation-induced cell killing when used as either a pulse exposure or a continuous treatment. In asynchronous populations of cells, this was expressed as an increase in the slope and a reduction in the shoulder of the radiation dose-survival curve. In synchronous populations of cells, a modest increase in cell killing was observed for those cells treated in G1 and G2, with a greater enhancement for cells treated in the S-phase. Overall, razoxane may potentiate the radiation-induced killing of cultured mammalian cells by a number of mechanisms: 1) a blockade of cell cycle progression causing an accumulation of cells in radiosensitive phases of the cell cycle; 2) selective cytotoxicity of cells in radioresistant phases of the cell cycle; 3) inhibition of the accumulation of sublethal radiation damage; or 4) interaction of the damages induced by each agent so as to produce an enhanced effect. These mechanisms may need to be considered if razoxane and radiation therapy are to be used in combined modality therapeutic approaches.

Animals↗
PubMed1986

Randomized trial of oral adjuvant razoxane (ICRF 159) in resectable colorectal cancer: five-year follow-up.

Razoxane is one of the few agents which has shown activity in the treatment of advanced colorectal cancer. The drug has therefore been evaluated in a prospective randomized controlled trial as an adjuvant to surgery for resectable colorectal cancer. The results to median follow-up of 5 years are reported here. Accrual has ceased and a total of 272 patients entered the trial (133 control, 139 treatment). Treated patients received razoxane postoperatively on a continuous, long-term basis while control patients received identical clinical care but no adjuvant chemotherapy. Analysis of the results shows a significant prolongation of the time to recurrence for Dukes' C patients. All other groups including the overall analysis show no benefit although there is a consistent trend in favour of the treated patients except in Dukes' group 'D'. Razoxane is tolerated well by patients and causes minimal side-effects. However acute leukaemia occurred in three patients (2.45 per cent) after prolonged exposure to the drug and further evaluation should be in patients who are at high risk of developing recurrent cancer, in whom such a risk may be acceptable. It is concluded that razoxane is suitable for further evaluation in colorectal cancer and for incorporation into combination chemotherapy regimens.

Clinical Trials as Topic↗
PubMedDate not supplied

Antimetastatic effects of razoxane in a rat osteosarcoma model.

The cytostatic and antimetastatic activities of 1,2-di(3,5-dioxopiperazin-1-yl) propane (ICRF-159, razoxane) were studied in a transplantable, slowly growing osteosarcoma in Sprague-Dawley rats. This tumor model is characterized by osteoid formation and spontaneous metastasization to lungs, kidneys and lymph nodes. Razoxane given intraperitoneally (i.p.) from 2 days before to 14 days after tumor transplantation (30 mg/kg or 10 mg/kg per day) resulted in a dose-dependent prolongation of median survival time (83 or 48 days respectively, versus 38 days for the control group), but showed no influence on the growth of the primary tumor. Early treatment with razoxane (30 mg/kg i.p. from day -2 to +14) showed a greater inhibition of pulmonary metastases than later treatment (30 mg/kg i.p. from day +14 to +28 after transplantation). Whereas 59.9 per cent of the total sectional area of the lungs in the control animals was covered by osteosarcoma metastases, only 3.4 per cent and 26.1 per cent respectively was affected in the early and late razoxane treatment groups. Toxic side-effects of these treatment schedules were reversible diffuse alopecia, but no retardation of body weight gain.

Animals↗
PubMed1982

Razoxane penetration into the cerebrospinal fluid of rats.

Razoxane (100 mg/kg) was administered to rats as a single IP dose. Plasma and CSF samples were obtained at intervals varying from 15 min to 24 h after dosing, and the razoxane was assayed by a new and simple high performance liquid chromatography (HPLC) technique. Razoxane was absorbed quickly from the peritoneal cavity; it reached a peak concentration within 0.5 h and decayed with a half-life of 1.6 h. Only 10% of the plasma razoxane available entered the CSF, reaching a peak concentration by 2h, which was maintained for a further 4 h, and finally decaying to reach 10% of its peak value by 8 h.

Animals↗
PubMed1994

Inoperable recurrent rectal cancer: results of a prospective trial with radiation therapy and razoxane.

PURPOSE: The effect of the sensitizer razoxane was prospectively evaluated in recurrent rectal cancer. Endpoints of the study were mainly local response rates and survival. METHODS AND MATERIALS: From 1984 to 1990 razoxane was given together with radiation therapy to 40 patients with recurrent inoperable rectal cancer. Loco-regional relapses in the pelvis were isolated in 24 and associated with distant metastases in 16 patients. Special attention was given to the subset of 24 patients with isolated local recurrences. This group was compared with historical controls treated with radiotherapy alone. The dosage of razoxane was 150 mg/m2 daily orally starting 5 days before the first irradiation. The drug was then given each radiation day until the end of treatment. The median radiation dose was 60 (40-62) Gy in the evaluable patients. The minimum follow-up was 32 months and the median 72 months. RESULTS: The rates of complete plus partial responses were 57% and 54%, respectively, for recurrent patients without and with distant metastasis. The 23 evaluable patients with isolated local relapses had a median survival of 24 months (12-94+); all patients surviving at least 1 year. CONCLUSION: The combination of radiotherapy and razoxane may lead to better local control and improved median survival compared to our historical controls and literature reports where radiotherapy alone was used. The treatment is easy to administer and is associated with a moderate toxicity.

Adult↗
PubMed1986

Phase I-II evaluation of razoxane (ICRF-159) and doxorubicin in gastrointestinal cancer. A Southeastern Cancer Study Group Trial.

A Phase I-II study of razoxane (ICRF-159) and doxorubicin was undertaken in 34 adults with advanced gastrointestinal carcinoma. Three dose schedules were studied; weekly razoxane at 600 mg/m2 orally plus doxorubicin 60 mg/m2 every 3 weeks, razoxane at 300 mg/m2 plus doxorubicin 60 mg/m2, and weekly razoxane 300 mg/m2 plus doxorubicin 35 mg/m2 every 3 weeks. This combination produced moderate to severe granulocytopenia in 24 patients including granulocytopenia less than or equal to 500/mm3 in 15. The granulocytopenia occurred regardless of prior chemotherapy and regardless of dose schedule employed. Two septic deaths were recorded but no responses. Further evaluation of this combination is not recommended.

Adenocarcinoma↗
PubMed1988

Phase I trial of cisplatin and razoxane (ICRF-159) (NSC #119875) in advanced squamous cell carcinoma of the cervix. A Gynecologic Oncology Group Pilot Study.

Both cisplatin and razoxane have shown activity in squamous carcinoma of the cervix. Cisplatin at a dose of 50 mg/m2 intravenously every 21 days was combined with razoxane at two dose levels--750 mg/m2 weekly and 1150 mg/m2 weekly. Three patients were treated at the first dose level and six patients were treated at the second dose level of razoxane. No objective regressions were observed, and three patients refused to continue therapy at the higher dose of razoxane because of nausea and vomiting. Further study of this regimen in cervical cancer is not recommended.

Adult↗
PubMed1982

Mitigating effects of ICRF-159 (razoxane) on a daunomycin-induced cardiomyopathy in mice.

In an attempt to induce in mice the cardiomyopathy associated with daunomycin treatment and to ameliorate this disorder by a protective pretreatment with ICRF-159 (razoxane), young male BDF 1 mice were injected with daunomycin, 6 mg/kg, in multiple doses. A second group of mice were pretreated by injection with razoxane, 200 mg/kg, 24 hours before each daunomycin administration. Within three weeks of the third daunomycin injection one half of the unprotected mice were moribund and were sacrificed. Mice pretreated with razoxane survived the length of the experiment without exhibiting any disabilities. Myocardial tissue of all mice was processed for light and electron microscopic examination. The myocardial ultrastructure of daunomycin-toxic mice showed foci of incipient changes, characterized by sarcoplasmic translucency, vacuolation of membrane-limited components, degeneration of mitochondria and lysosomal aggregates. Evaluation of mice pretreated with razoxane either failed to reveal ultrastructural alterations or demonstrated only minimal changes in the myocardium.

Animals↗
PubMed1992

Sister chromatid exchange (SCE) frequency in lymphocytes of patients with colorectal carcinoma treated with razoxane.

The increased risk of neoplasia following cytotoxic therapy for both malignant and nonmalignant disease is well known. Sister chromatid exchange (SCE) frequencies in patients receiving such chemotherapy are often elevated, and the persistence of high levels after treatment may provide an indicator for susceptibility to secondary neoplasia. The cytostatic drug razoxane has been used for the treatment of psoriasis, acute myeloid leukemia (AML), and colorectal carcinoma. Prolonged use of this drug, however, has been associated with the subsequent development of AML and, up to November 1987, 16 cases of acute leukemia following razoxane treatment have been reported. We report the SCE frequencies for 34 patients with colorectal carcinoma who were receiving or had previously been treated with razoxane. Our results show no significant increase in SCE levels in the razoxane group compared with either normal controls or untreated patients.

Acute Disease↗
PubMedDate not supplied

Effect of razoxane on metastases from colorectal cancer.

At a median follow-up of 5 years, adjuvant razoxane (125 mg b.d.) given 5 days/week indefinitely following resection of colorectal cancer provided no benefit in terms of survival or recurrence for Dukes' A or B patients when compared to untreated controls. However in Dukes' C patients this treatment reduced the recurrence rate (P = 0.05) and possibly increased survival time (P = 0.08). Analysis now of the development of metastases in this trial which entered 272 patients over 7 years shows that in the Dukes' C group the incidence of liver metastases in the razoxane-treated patients is only about half that of the untreated patients (18 per cent versus 34 per cent) and that the time to first appearance of the liver metastases is twice as long in the razoxane-treated group as it is in the untreated group (80 weeks versus 40 weeks). It is concluded that the benefit of adjuvant razoxane observed in the Dukes' C patients is due to the antimetastatic activity of the drug in reducing and slowing down the development of hepatic secondaries.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1987

Reduction of chronic doxorubicin cardiotoxicity in beagle dogs by bis-morpholinomethyl derivative of razoxane (ICRF-159).

Addition of morpholinomethyl substituents to razoxane (ICRF-159) produced a compound (bis-4-morpholinomethyl-3,5-dioxopiperazinyl-1,2-propane (MM-159) considerably more water-soluble than razoxane. The increased solubility allowed MM-159 to be examined for protective activity against chronic doxorubicin (DXR) cardiotoxicity. Adult beagle dogs of either sex were given, i.v. at 3-week intervals, either DXR (1.75 mg/kg) alone or DXR 15 min after MM-159 (25 mg/kg). Control animals received MM-159 (25 mg/kg) or saline without DXR. The experiment was terminated 3 weeks after the ninth injection (total DXR dose, 15.75 mg/kg). Of the eight animals given DXR alone, five died after receiving seven to eight injections (12.25-14 mg/kg DXR) and the remaining three were killed after eight injections because they were in poor condition. Marked ascites was noted in four of these eight dogs. When frequency and extent of myocardial lesions (vacuolation and myofibrillar loss) were assessed on a scale from 0 to 4+, severe lesions (3+) were present in all eight dogs given DXR alone, but no abnormalities (lesion score 0) were found in the hearts of three of eight dogs given MM-159 and DXR and the five remaining animals in this group had minimal (1+; four dogs) or mild (2+; one dog) alterations. DXR reduced the erythrocyte count, hemoglobin, and hematocrit when administered alone, but not in combination with MM-159. Such protection against DXR hematologic effects was not noted previously when dogs were pretreated with ICRF-187, the d-isomer of razoxane, despite the fact that pretreatment with ICRF-187 was as effective as MM-159 in reducing chronic DXR cardiotoxicity. It remains to be determined whether there are other differences in biological activity between MM-159 and ICRF-187.

Animals↗
PubMedDate not supplied

Effects of rotational stress on the effectiveness of cyclophosphamide and razoxane in mice bearing Lewis lung carcinoma.

The effects of conventional vs protected housing, and those caused by the periodic application of a psychological stressor (rotational stress, spatial disorientation) on mice kept in a protected housing, with spontaneous tumor metastasis have been determined in mice implanted with Lewis lung carcinoma as a function of tumor inoculum size and response to treatment with cyclophosphamide and razoxane. With a reduced inoculum size, tumor takes do not occur in mice kept in the protected housing, but do occur with spatial disorientation. With a larger inoculum size, tumor takes occur in all untreated mice, and the weight of spontaneous lung metastasis is significantly increased by spatial disorientation. For mice in protected housing, cyclophosphamide results in the absence of macroscopically detectable tumors in all of the treated mice, whereas the use of spatial disorientation abolishes this therapeutic action. The antimetastatic effects of razoxane are also reduced by rotational stress. These results indicate that housing conditions and a psychological stressor can control tumor takes and metastasis formation. They also indicate that host's antitumor resistance effectors, which are susceptible to neuroendocrine modulation by environmental and psychological stressors, participate to determine the effectiveness of the treatment with a cytotoxic (cyclophosphamide) and antimetastatic (razoxane) antitumor drug.

Animals↗