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PubMed1979

[Drug interaction on antitumor drugs I. Antitumor activity of cyclophosphamide in mice consecutively administered aminopyrine, chlorpromazine, or morphine (author's transl)].

Antitumor activity and lethality of cyclophosphamide alone and in combination with several drugs were investigated in male ddY mice. The antitumor activity was estimated by weighing the solid tumor on the 15th day after Ehrlich ascites cell inoculation. Pentobarbital induced sleeping time for monitoring the activity of hepatic drug-metabolizing enzymes was defined as the time between the loss and the recovery of the righting reflex. Consecutive administration of pentobarbital shortened the pentobarbital sleeping time and increased the antitumor activity after cyclophosphamide. On the contrary, a single administration of SKF 525A or cycloheximide prolonged the pentobarbital sleeping time significantly and decreased the antitumor activity after cyclophosphamide. Consecutive administration of aminopyrine, or chlorpromazine shortened the pentobarbital sleeping time and increased the antitumor activity after cyclophosphamide. These results indicate that aminopyrine and chlorpromazine may increase the levels of the hepatic drug-metabolizing components and may activate cyclophosphamide by conversion to an active form. Effect of a consecutive administration of morphine on the pentobarbital sleeping time and the antitumor activity was uncertain in individual cases. On the other hand, aminopyrine, chlorpromazine, or morphine in consecutive administration increased the lethality of cyclophosphamide.

Aminopyrine↗

PubMed1978

Cross-linking of DNA in L1210 cells and nuclei treated with cyclophosphamide and phosphoramide mustard.

Phosphoramide mustard, formed from cyclophosphamide in vivo and in vitro, may be the active metabolite of this drug. We have found phosphoramide mustard to be at least 100 times more potent than cyclophosphamide in inhibiting growth of two strains of the L1210 lymphoma in culture. Phosphoramide mustard also produced enlargement of cells, an effect not seen with cyclophosphamide. Phosphoramide mustard significantly increased the amount of cross-linked DNA after incubation with intact LM4 cells or nuclei isolated from these cells. Cyclophosphamide had a similar effect only in the isolated nuclei. These findings strengthen the proposed role of phosphoramide mustard as the active metabolite of cyclophosphamide. The effect of cyclophosphamide on nuclei is unexplained.

Alkylation↗

PubMed1984

Combined cyclophosphamide chemotherapy and maltose tetrapalmitate immunotherapy in the treatment of transplanted bladder and prostate carcinoma of the rat.

Chemoimmunotherapy in two animal models for urological cancers was studied. The models were Dunning R3327A prostatic carcinoma transplanted s.c. in Fischer X Copenhagen F1 hybrids and a well-differentiated bladder carcinoma transplanted orthotopically in the bladder submucosa of female Fischer rats. Cyclophosphamide, cis-platinum, and Adriamycin were initially used as anticancer chemotherapeutic agents, and the most effective ones were used in combination with maltose tetrapalmitate (MTP), which was used as an immunopotentiator. In the case of prostatic carcinoma, cyclophosphamide was the most effective among the anticancer agents in controlling tumor growth after inoculation of either 10(4) or 10(5) tumor cells. Combination of cyclophosphamide with i.p. MTP delayed tumor take and controlled tumor size more effectively than did either of the treatments given alone. Similar results were obtained in the case of bladder tumor. A combination of cis-platinum with MTP significantly controlled bladder tumor size, and a combination of cyclophosphamide with MTP cured 75% of the rats. The remaining 25% of this group had a small tumor that did not increase in size during the subsequent 2 weeks of observation without treatment. The incidence of metastasis of bladder tumor to lymph nodes and lung was reduced by MTP and cis-platinum and eliminated by cyclophosphamide alone and in combination with MTP. Nonspecific immunity as measured by phytohemagglutinin stimulation of spleen lymphocytes and antitumor immunity as measured by cytotoxicity and macrophage migration inhibition assays were highest in rats subjected to cyclophosphamide and MTP combined therapies.

Animals↗

PubMedDate not supplied

Chronobiologic fluctuation of cyclophosphamide induced urinary bladder damage in mice.

Cyclophosphamide is the most widely used alkylating agent in clinical medicine. The usefulness of this drug is often limited by its propensity to produce hemorrhagic cystitis. To be active cyclophosphamide must be metabolized by the mixed function oxidase system. It has been previously demonstrated that the oncolytic activity and host lethality of cyclophosphamide are dependent upon circadian fluctuations. When cyclophosphamide is administered i.p. to male mice there is a dose dependent increase in urinary bladder weight. Histopathologic examination of these bladders revealed hemorrhage, edema, inflammation and stretching of the epithelial lining. When administered i.p. at 4-h intervals throughout a 24-h time period, cyclophosphamide produced maximum bladder damage when administered at 0500 and 1700 and little or no damage to the bladder when administered at 0100 or 1300. These studies suggest that cyclophosphamide induced cystitis, a toxicity resulting from the metabolic production of acrolein, may also be dependent upon chronobiologic fluctuations.

Animals↗

PubMed1983

Comparison of effects of daily versus hyperfractionated split-course radiation schedules with and without cyclophosphamide on median survival, metastatic dissemination, tumor cure, and growth rates.

Daily fractions of 188, 250, 375, 500, and 750 rads were given to rats with hepatoma 3924A so that all groups received the same weekly dose of 1500 rads over a 6-week period, for total doses of 9000 rads when only radiation was given and 4500 rads when combined with cyclophosphamide. No tumors were cured (with two exceptions) with or without three doses of cyclophosphamide (150 mg/kg or 0.9 g/sq m) given 14 days apart. The addition of cyclophosphamide to the daily radiation treatment schedules did not change the time for tumors to reach 8 times the volume at time of treatment but did result in a longer median survival, which was attributed to a reduction of pulmonary metastases. A hyperfractionated radiation schedule using six 250-rad fractions given three times daily every 4 hr for 2 days combined with cyclophosphamide (150 mg/kg) 1 day later and repeated two additional times at 11-day intervals for a total dose of 4500 rads and cyclophosphamide (450 mg/kg) resulted in eradication of six of ten tumors, for a cure rate of 60%. Skin damage, determined by visually scoring the skin, appeared to be fully recovered by Day 126 and remained so until the end of the experiment on Day 384. The three courses of hyperfractionated radiation (total dose, 4500 rads), when given alone, were ineffective in producing tumor regression and cure. Combining cyclophosphamide with hyperfractionated split-course radiation schedules gave a major increase in tumor cure rate as compared with radiation alone at the same (4500 rads) or higher (9000 rads) doses. The major gains in effective utilization of the two modalities is greatly diminished or lost when the radiation is administered as daily fractions.

Animals↗

PubMed1983

Effects of combination estrogen:cyclophosphamide treatment on the growth of the MXT transplantable mammary tumor in the mouse.

The present studies were done to determine if the growth-promoting properties of estrogen on the MXT transplantable mammary tumor in the mouse would enhance the cytotoxicity of cyclophosphamide. Mice bearing these tumors had beeswax pellets implanted which contained 17 beta-estradiol (0.01 to 1.0 mg/pellet) and/or injected twice weekly with cyclophosphamide (10 to 40 mg/kg body weight in sesame oil) for 4 to 7 weeks. During this time, tumor size [(L + W)/2] and body weights were monitored every 7 to 14 days. The results show that administration of estradiol (0.01 to 1.0 mg/pellet) by implant slightly stimulated tumor growth, and in no case was tumor regression observed in response to the steroid. Likewise, cyclophosphamide treatment alone (10 to 20 mg/kg) failed to inhibit the tumor; however, combined administration of estradiol plus cyclophosphamide (10 to 40 mg/kg) resulted in significant inhibition of tumor growth. This response was time and dose dependent. These results show that while neither compound alone inhibited tumor growth, estradiol and cyclophosphamide are synergistic and completely block the growth of this transplantable mammary tumor in the mouse. The mechanism for this antagonism of mammary tumor growth remains to be resolved; however, we speculate that estradiol stimulates cellular hypertrophy and hyperplasia in these tumors, and under these conditions the cytotoxic effectiveness of cyclophosphamide is enhanced.

Animals↗

PubMed1981

Comparison of vincristine utilized simultaneously or 24 hours before cyclophosphamide in maintenance regimen of acute lymphoblastic leukemia of children: a report of Childrens Cancer Study Group.

A controlled clinical study in children with lymphoblastic leukemia was conducted to measure the potential benefit of time sequencing vincristine and cyclophosphamide. Vincristine and cyclophosphamide were utilized in a maintenance regimen in children after a remission had been obtained. Patients received vincristine either 24 hours before cyclophosphamide or simultaneously with cyclophosphamide. The median time to relapse and the number of continued remissions was significantly increased for patients receiving vincristine 24 hours before cyclophosphamide when compared to those patients receiving both drugs simultaneously. The results of this comparative study indicate that the sequential use of vincristine and cyclophosphamide for maintenance of a second relapse in childhood ALL produces a greater duration of remission than when both are used simultaneously.

Adolescent↗

PubMed1980

The embryotoxic effects of cyclophosphamide in rabbits tested in vivo by i.v. injection and by the yolk-sac method.

On the 9th day of gestation of rabbits the embryotoxic effects of cyclophosphamide were tested in vivo by i.v. injection (20, 40 and 80 mg/kg) and by injection into the yolk sac of rabbit embryos (20 micrograms, 80 micrograms 320 micrograms/blastoderm; yolk-sac-method). Furthermore pharmacological studies were undertaken to investigate cyclophosphamide and its metabolism in the blastoderm (york sac fluid and embryo). When applied by i.v. injection, cyclophosphamide was embryolethal and teratogenic in a dose-dependent manner. No embryotoxic effects could be observed by injection of unchanged cyclophosphamide into the yolk sac of rabbit embryos. Pharmacokinetic studies did not show any metabolism in the blastoderm by injection or unchanged cyclophosphamide into the yolk sac. The embryotoxicity of unchanged cyclophosphamide is discussed.

Abnormalities, Drug-Induced↗

PubMed1995

Dose-finding study of paclitaxel and cyclophosphamide in patients with advanced breast cancer.

Escalating doses of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) (administered as a 3-hour infusion) and cyclophosphamide have been given to patients with advanced breast cancer every 3 weeks to determine the maximum tolerated dose of the two drugs in combination without granulocyte colony-stimulating factor (G-CSF) support. The maximum tolerated dose of the same regimen with G-CSF support will then be determined in a subsequent group of patients. Patients who had received no more than one prior chemotherapy regimen for advanced disease were eligible for this study. The need for G-CSF support was established by an absolute neutrophil count (ANC) less than 0.5 x 10(9)/L for more than 7 days, an ANC count less than 0.1 x 10(9)/L for more than 3 days, febrile neutropenia requiring intravenous antibiotics, World Health Organization grade 3 or greater mucositis for more than 7 days, or the failure of the ANC to recover by day 28. The maximum tolerated dose was defined as the dose level at which more than two of six patients treated needed G-CSF support during the second treatment cycle. To date, 20 patients have been entered at the following dose levels: paclitaxel 135 mg/m2 and cyclophosphamide 750 mg/m2 (level 1), paclitaxel 155 mg/m2 and cyclophosphamide 750 mg/m2 (level 2), paclitaxel 175 mg/m2 and cyclophosphamide 600 mg/m2 (level 3), and paclitaxel 175 mg/m2 and cyclophosphamide 750 mg/m2 (level 4). Only one patient at level 2 needed G-CSF support because of an ANC below 0.1 x 10(9)/L for more than 3 days after the first cycle. Neither febrile neutropenia nor treatment delay for more than 1 week was reported. Antitumor activity has been observed from level 3. The evaluation of the toxicity of paclitaxel 200 mg/m2 and cyclophosphamide 175 mg/m2 without G-CSF support is ongoing.

Adult↗

PubMed1995

Effect of cyclophosphamide on the binding of 99mTcO-4 and 99mTc-MDP to blood cells and plasma proteins.

Since the introduction of technetium-99m (99mTc) and its rapid acceptance as a tool in nuclear medicine, very little information is available about its biological action as 99mTc-radiopharmaceuticals. We have determined if cyclophosphamide, an alkylating agent, used in oncology as a chemotherapeutic drug, modifies the binding of 99mTcO-4 and 99mTc-MDP (99mTc-methylenediphosphonic acid) to blood cells and to plasma proteins. The radiopharmaceuticals were injected intravenously (iv) into SW-55 mice (male and female, weight 25 g) and samples of plasma and blood cells were separated. Cyclophosphamide (50 micrograms) was injected iv 1 h before the radiopharmaceuticals. Samples of plasma and blood cells were also precipitated with 5% trichloroacetic acid and soluble and insoluble fractions were isolated. The following results were obtained: 1) cyclophosphamide did not alter (0.25 to 8 h) percent radioactivity of 99mTcO-4 in plasma or blood cells but increased the binding of 99mTc-MDP to blood cells; 2) cyclophosphamide did not alter (0.25 to 8 h) the binding of 99mTcO-4 in insoluble fraction of plasma and decreased (1 to 4 h) percent radioactivity of 99mTc-MDP in the insoluble fraction of plasma; 3) cyclophosphamide increased (0.25 to 4 h) percent radioactivity of 99mTcO-4 in the insoluble fraction of blood cells but did not alter the binding of 99mTc-MDP. Cyclophosphamide and/or its metabolites modified the effective half-life of these radiopharmaceuticals (to 99mTcO-4 was increased 2.3 to 3.4 h and to 99mTc-MDP was decreased 3.3 to 2.1 h) and possibly increased the permeability of blood cells to 99mTcO-4.

Alkylating Agents↗

PubMed1995

Pulse cyclophosphamide therapy for refractory autoimmune thrombocytopenic purpura.

Autoimmune thrombocytopenic purpura (AITP) is generally a chronic disorder in affected adults. Twenty-five percent of these patients will become refractory to routine therapy (corticosteroids and splenectomy), as well as most other available agents. Intravenous pulse cyclophosphamide therapy was used to treat 20 patients with severe refractory AITP who had previously failed to achieve a sustained remission with a mean of 4.8 agents (range 2 to 8). Patients received 1 to 4 doses (mean 2.0) of 1.0 to 1.5 g/m2 intravenous cyclophosphamide per course. Of the 20 patients treated with pulse cyclophosphamide therapy, 13 patients (65%) achieved a complete response (CR), four (20%) a partial response (PR), and three patients (15%) failed to respond. Of the 13 complete responders, eight have remained in remission with stable platelet counts during followup intervals of 7 months to 7 years (median 2.5 years). Five patients developed recurrent AITP 4 months to 3 years following a CR. Of these, two patients responded to subsequent courses of pulse cyclophosphamide therapy with current remissions of 1 and 4 years. Of the four patients who obtained a PR, two remain in partial remission after 10 months and 4 years; one relapsed after 18 months and, after retreatment, is still in remission at 6 months. Of the patient characteristics examined, duration of disease was most strongly associated with response to pulse cyclophosphamide. Side-effects of treatment included neutropenia (three patients, one of whom developed staphylococcal sepsis), acute deep venous thrombosis (two patients), and psoas abscess (one patient). Intravenous pulse cyclophosphamide should be strongly considered in the treatment of patients with refractory AITP. There is a relatively low incidence of side-effects, and it can be administered easily on an out-patient basis.

Adolescent↗

PubMed1993

Cyclosporin versus cyclophosphamide for patients with steroid-dependent and frequently relapsing idiopathic nephrotic syndrome: a multicentre randomized controlled trial.

OBJECTIVE: To compare the efficacy (maintenance of remission), safety and tolerability of cyclosporin (CsA) with those of cyclophosphamide in patients with steroid-dependent or frequently relapsing nephrotic syndrome (NS). DESIGN: Open, prospective, randomized, multicentre, controlled study for parallel groups, stratified for adults and children. The setting was in nephrological departments in Italy. SUBJECTS AND INTERVENTIONS: Seventy-three patients with steroid-sensitive idiopathic NS admitted to the study were randomly assigned to cyclophosphamide (2.5 mg/kg/day) for 8 weeks or CsA (5 mg/kg/day in adults, 6 mg/kg/day in children) for 9 months, tapered off by 25% every month until complete discontinuation at month 12. Seven patients lost to follow up were not considered in the analysis. The remaining 66 patients were followed up for 3-24 months after randomization. MAIN OUTCOME MEASURES: Relapse-free survival; number of N.S. relapses/patient/year; cumulative dose of prednisone/patient; laboratory investigations (kidney and liver functions, haematological parameters); incidence of adverse events. RESULTS: At month 9, 26 of 35 CsA-treated patients were still in complete remission and a further five patients were in partial remission; 18 of 28 cyclophosphamide-treated patients were in complete remission, and one in partial remission (P = NS). No difference between adults and children was seen with either treatment. The risk of relapse was similar between frequent relapsers (19 of 22) and steroid-dependent patients (8 of 14) given CsA, and those given cyclophosphamide (5 of 15 and 6 of 15). The mean number of relapses per year and the mean dose of prednisone per year were significantly less (P < 0.001) in both groups for the experimental year than for the year before randomization. At 2 years, 25% of the patients given CsA (50% adults and 20% children) and 63% of those given cyclophosphamide (40% adults and 68% children) had not had any relapse of NS. Tolerance to the two drugs was generally good. The CsA-related side-effects were mild and disappeared after drug discontinuation. CONCLUSIONS: This study shows that both treatments are effective and well tolerated; more patients given cyclophosphamide had stable remissions.

Adolescent↗

PubMed1995

Protective effect of the thiol agent WR-2721 against cyclophosphamide-induced cytotoxicity in the mouse erythropoietic system.

The effect of WR-2721 against cyclophosphamide-induced cytotoxicity was studied using the mouse micronucleus test. Adult male Swiss mice were treated intraperitoneally with a dose of 200 mg/kg or 400 mg/kg b.w. WR-2721, 15 or 30 minutes prior to cyclophosphamide administration, with a dose of 200 mg/kg b.w. The frequency of micronuclei in polychromatic erythrocytes and the number of polychromatic erythrocytes in the peripheral blood were determined 24-hours after CP treatment. In comparison with the controls, in mice injected with cyclophosphamide, the number of micronucleated polychromatic erythrocytes was increased, and the number of polychromatic erythrocytes was decreased. In mice treated with WR-2721 and CP, in relation to those injected with cyclophosphamide alone, the frequency of micronuclei in polychromatic erythrocytes was lower, but the number of polychromatic erythrocytes was found to be greater. The protective effect of WR-2721 against cyclophosphamide-induced clastogenicity and suppressing mitotic activity of the erythropoietic system caused by the alkylating drug was shown. The effect was dependent on the dose of the thiol compound applied and it was more expressive when WR-2721 was given in the higher dose, 400 mg/kg b.w. However, the protection by aminothiol appeared not to depend on the time intervals between WR-2721 and CP administration into mouse organism. The result may be useful for therapeutic application of WR-2721 with cyclophosphamide therapy.

Amifostine↗

PubMed1996

Clinical, biochemical and pathological predictors of poor response to intravenous cyclophosphamide in patients with proliferative lupus nephritis.

BACKGROUND: Reports in the literature on the outcome of lupus nephritis (LN) treated with intravenous (i.v.) cyclophosphamide have varied considerably. Previous studies have suggested that less than 25% of patients with LN will progress to end stage renal failure (ESRD) after 5 years. In addition it has been reported that serum creatinine and chronic histologic changes on kidney biopsy are useful markers of renal prognosis. Whether treatment with cyclophosphamide alters the predictive value of these markers in LN patients is not clear. The aim of this study was to review our experience of treating a large cohort of patients with LN treated with i.v. cyclophosphamide and to identify biochemical and histological features at the time renal biopsy which predict outcome in these patients. DESIGN: We retrospectively reviewed our experience with 43 consecutive patients who met criteria for either World Health Organization (WHO) classification III (focal proliferative) or IV (diffuse proliferative) LN and were treated with monthly i.v. cyclophosphamide. Biochemical indices of renal function and lupus disease activity were recorded. Renal biopsies, performed within two months of commencing therapy, were reviewed by two experienced pathologists and classified according to WHO classification as well as activity and chronicity index. The primary outcome variable for the analysis was the development of ESRD. RESULTS: Patients were followed for a mean of 2 years after renal biopsy. The mean dose of cyclophosphamide received by patients was 8.3 g. One patient died during follow up and 22 (51%) progressed to ESRD. A higher serum creatinine (p = 0.003) and higher score for interstitial fibrosis (p = 0.001) were associated with shorter renal survival. There was no significant association between activity index or its components or in the total chronicity score and survival free from the need for dialysis. CONCLUSION: In our experience more than half of patients treated with i.v. cyclophosphamide for LN progress to ESRD and a high serum Cr and a high degree of interstitial fibrosis on renal biopsy before treatment are associated with a worse renal prognosis.

Adult↗

PubMed1997

Cyclophosphamide as alternative immunosuppressive therapy for autoimmune hepatitis--report of three cases.

Autoimmune hepatitis is a chronic inflammatory disorder of the liver with a fluctuating course, which often requires long-term immunosuppressive therapy in order to prevent fibrosis to the liver. The mainstay of immunosuppressive therapy is the use of corticosteroids, usually in conjunction with azathioprine. However, in a subgroup of patients with severe side effects or intolerance of standard therapy there is a need for alternative immunosuppressive agents. We describe the successful long-term treatment of three patients with severe autoimmune hepatitis with an immunosuppressive regimen consisting of cyclophosphamide and corticosteroids. In the reported patients we were able to induce remission with cyclophosphamide in a dose of 1-1.5 mg/kg bodyweight in combination with a tapering dose of corticosteroids beginning with 1 mg/kg bodyweight. After induction we were able to maintain histology proven remission with low doses of corticosteroids (2.5-10 mg/day) together with 50 mg of cyclophosphamide every other day. With this dose of cyclophosphamide we have neither observed relapse of autoimmune hepatitis nor severe side effects in a cumulative observation period of more than twelve years in the three patients. As a consequence of our favourable experience with cyclophosphamide in the reported cases, we propose cyclophosphamide as an alternative to azathioprine in cases of autoimmune hepatitis with severe side effects of intolerance of standard therapy.

Adult↗

PubMed1998

p53 mutations in cyclophosphamide-associated bladder cancer.

Cyclophosphamide is a known bladder carcinogen, with cumulative dose directly related to increased risk. There is no consensus, however, on which major cyclophosphamide metabolite (i.e., acrolein or phosphoramide mustard) drives bladder carcinogenesis. We examined 19 cyclophosphamide-related bladder tumors to test the hypothesis that they might contain somatic mutations in the p53 tumor suppressor gene that could link a specific metabolite to the etiology of these cancers. Forty-three % (9 of 19) of the cases had a mutation in p53, with a predominance at G:C bp (7 of 9, 77%), a preference for non-CpG sites (6 of 7, 86%), and frequent G:C-->A:T transitions (5 of 7, 71%). The p53 mutation spectrum of these cyclophosphamide-associated bladder cancers differed significantly from patterns reported for sporadic (P = 0.020), smoking-related (0.043), and schistosomiasis-linked (P = 0.002) tumors but not arylamine-associated neoplasms (P = 0.860). Differences between the cyclophosphamide and arylamine-associated spectra included an unusual degree of clustering of exon 6 mutations (43% versus 17%, respectively) and an absence of multiple mutations in the former. Notably lacking in our series were G:C-->T:A transversions, the principal mutation associated with acrolein. Instead, the mutation spectrum matches the phosphoramide mustard adduction sequences determined by a repetitive primer-extension assay (P = 0.024), indicating that this metabolite might be a key mutagen in cyclophosphamide-related bladder cancer.

Adult↗

PubMed1998

The salubrious effects of ascorbic acid on cyclophosphamide instigated lipid abnormalities in fibrosarcoma bearing rats.

The combined effect of cyclophosphamide and ascorbic acid on plasma lipids and lipoprotein profiles are important since, ascorbic acid encumbered the lipid abnormalities initiated by cyclophosphamide during cancer chemotherapy. Hence, the study was launched to appraise the salutary role of ascorbic acid in cyclophosphamide administered fibrosarcoma bearing rats. Fibrosarcoma cell line induced rats were treated with cyclophosphamide (10 mg/kg body weight) and ascorbic acid (200 mg/kg body weight) individually and in combination for 28 days. The concentration of plasma lipids and lipoprotein profiles were determined in control and experimental animals. The untreated, as well as cyclophosphamide administered fibrosarcoma bearing rats, divulged significantly increased levels of plasma total cholesterol, triglycerides, phospholipids, VLDL- and LDL-cholesterol, as compared with their respective control animals. In contrast, ester and HDL-cholesterol levels exhibited a marked decrease in these animals. Similar observations were also noticed in liver lipid values, as well. However, these lipid abnormalities were corrected by the co-administration of ascorbic acid. These results suggested, that some clinical entanglement of cyclophosphamide was refrained by co-administration of ascorbic acid in tumor stress condition.

Animals↗

PubMed2001

Phase I trial of i.v. administered tirapazamine plus cyclophosphamide.

Our objective was to determine the maximum tolerated doses of tirapazamine and cyclophosphamide given i.v. in combination. Eligible patients had advanced solid tumors refractory to conventional treatment. Tirapazamine (escalated from 80 to 390 mg/m(2)) was given i.v. over 2 h and followed by cyclophosphamide over 1 h. The cyclophosphamide dose was fixed at 1000 mg/m(2) until the tirapazamine dose of 390 mg/m(2) was reached. Once that dose of tirapazamine was reached, the cyclophosphamide dose was escalated to 1250 and 1500 mg/m(2). Twenty-eight patients were enrolled. The dose-limiting toxicity was granulocytopenia. One patient had transient deafness for 2 days. Four other patients had grade 1 ototoxicity. Grade 1 and 2 muscle cramps were observed at all dose levels. Other toxic effects observed included fatigue, nausea, vomiting, headache, diarrhea, drug fever, elevated transaminases and elevated creatine phosphokinase. Three patients had stable disease and the longest time to progression was 5 months. The combination of tirapazamine and cyclophosphamide is feasible, and the dose-limiting toxicity is granulocytopenia. The use of growth factors could possibly allow escalation of tirapazamine doses in future phase II trials. Without growth factor support, the recommended doses of tirapazamine and cyclophosphamide when administered in this schedule are 260 and 1000 mg/m(2), respectively.

Adult↗