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PubMed1986

Pharmacokinetics of intraventricular and intravenous N,N',N''-triethylenethiophosphoramide (thiotepa) in rhesus monkeys and humans.

The cerebrospinal fluid (CSF) and plasma pharmacokinetics of N,N',N"-triethylenethiophosphoramide (thiotepa), an alkylating agent used for treatment of carcinomatous meningitis, were determined in rhesus monkeys in order to assess the relative advantage of intraventricular versus systemic administration of the drug. Following an i.v. thiotepa dose of 0.9 mg/kg (11 mg/sq m), peak plasma levels of parent drug reached approximately 1 microgram/ml. Thiotepa was rapidly equilibrated with lumbar and ventricular CSF. Systemic, lumbar, and ventricular exposure to the drug, measured as area under the curve (AUC), were similar in all cases. After a 1-mg intraventricular dose of thiotepa, peak ventricular levels were greater than 100 micrograms/ml. However, peak levels in the lumbar CSF at 1 h after intraventricular administration were less than 10 micrograms/ml. The AUC for ventricular CSF was nearly 100-fold greater for the intraventricular route than for the i.v. route; however, the AUC for lumbar CSF following intraventricular delivery was only 5% of the AUC for ventricular CSF. N,N',N''-Triethylenephosphoramide, an active metabolite of thiotepa observed in all fluids, appeared to have a much slower total body clearance than thiotepa. Comparison of the data obtained from monkey experiments with data from a patient with meningeal disease supports the use of the monkey as a model for intraventricular pharmacokinetics. The data presented indicate that there is no relative advantage to intraventricular administration of thiotepa at the doses currently used in clinical trials.

Animals↗
PubMed1987

Pharmacokinetics of continuous-infusion high-dose thiotepa.

The pharmacokinetics of thiotepa administered as a continuous infusion over 4 days have been studied in 18 patients receiving high-dose thiotepa, cyclophosphamide, and autologous bone marrow reinfusion as treatment for advanced neoplasms. Patients received cyclophosphamide at a total dose of 6 g/m2 and thiotepa at a total dose of 180-900 mg/m2 over the 4-day infusion. Samples of plasma were obtained during and following infusion, and the plasma concentration of thiotepa was determined by the method of Egorin et al. For many patients (72%), peak concentrations of plasma thiotepa were achieved during the initial 24 hours of infusion and then declined an average of 29% by the end of the 96-hour infusion. The average total systemic clearance of thiotepa was 16.7 +/- 7.4 (SD) L/m2/hour [or 420 +/- 162 (SD) ml/kg/hr]. An inverse correlation between the average total systemic clearance and the dose of thiotepa was observed (P less than 0.01).

Adult↗
PubMed1984

Plasma pharmacokinetics and tissue distribution of thiotepa in mice.

We defined the plasma and tissue concentrations and pharmacokinetics of thiotepa in 22.8-29.3-g male Swiss-Webster mice injected iv with thiotepa at a dose of 5 mg/kg. Concentrations of thiotepa in ethyl acetate extracts of tissue and plasma were determined by gas chromatography. Plasma concentrations of thiotepa declined in a biexponential fashion that was well-described by the equation: Ct = 52.03e-3.36t + 3.10e-0.072t, indicating an alpha-half-life of 0.21 mins and a beta-half-life of 9.62 mins. Thiotepa was rapidly and extensively distributed through the tissues studied and was not concentrated in any particular tissue, although the liver consistently contained concentrations of thiotepa much lower than any other tissue studied. By 1 hr after injection, there was little thiotepa in plasma or any tissue.

Animals↗
PubMed1996

A study of thiotepa, etoposide and fractionated total body irradiation as a preparative regimen prior to bone marrow transplantation for poor prognosis patients with neuroblastoma.

We report the toxicity and efficacy of a new conditioning regimen for bone marrow transplantation (BMT) in children with poor prognosis neuroblastoma (NBL). Twenty-seven patients with poor prognosis NBL were treated with teniposide (360 mg/m2) or etoposide (500 mg/m2), thiotepa (600-900 mg/m2), and 1200 cGy fractionated total body irradiation (fTBI) followed by autologous marrow rescue (n = 19) or allogeneic BMT from HLA-identical siblings (n = 8). The two patients who received teniposide, 600 mg/m2 thiotepa and fTBI had minimal toxicity but relapsed 4 and 12 months post-auto BMT. The next two patients received 750 mg/m2 thiotepa, 500 mg/m2 etoposide and TBI. They tolerated the conditioning regimen well and are alive and in remission 77 and 75 months post-BMT. At the next thiotepa dose level (900 mg/m2), the first two allograft recipients both experienced fatal regimen-related toxicity. All subsequent allograft recipients received 750 mg/m2 thiotepa and autograft recipients received 900 mg/m2 thiotepa. As of 1 April 1995, eight of the 19 patients who received autologous marrow are surviving disease-free 21 to 77 months post-BMT. Nine autograft recipients relapsed at 2 to 37 months following transplantation. One patient died of hepatic veno-occlusive disease 2 months after auto BMT, and one of pneumonia 6 months post-transplantation. Three allograft recipients have relapsed at 6, 10 and 39 months post-transplant and three are alive and in remission 75, 53 and 27 months post-BMT. Overall, 11/27 patients (41%) are alive and in remission 21-77 months (median 47 months) following BMT. A conditioning regimen consisting of 500 mg/m2 etoposide, thiotepa (750 mg/m2 for allograft recipients and 900 mg/m2 for autograft recipients) and 1200 cGy fTBI has acceptable toxicity and is at least as effective as melphalan-containing regimens in the treatment of high-risk NBL.

Adolescent↗
PubMed1997

Thiotepa for the treatment of thrombocythemia in patients with Philadelphia chromosome positive chronic myelogenous leukemia.

BACKGROUND: Patients with chronic myelogenous leukemia (CML) occasionally experience persistent thrombocythemia despite having adequate white blood cell (WBC) counts. Trimethylenethiophosphoramide (thiotepa) is an alkylating agent that significantly inhibits platelet production. METHODS: The authors studied the effects of thiotepa in eight patients with CML with persistent thrombocythemia. All patients had adequate WBC counts while receiving therapy for leukemia. The median age of the patients was 58 years, and all had received at least 2 prior therapy regimens for CML. Thiotepa was administered by intravenous infusion at a dose of 75 mg/m2 once every 2 to 3 weeks; doses were adjusted according to hematologic response. RESULTS: Seven patients were evaluable for response to thiotepa. Their pretreatment median platelet count was 1215 x 10(9)/L. After receiving the first dose, 6 patients (86%) had favorable responses as the median platelet count dropped to 348 x 10(9)/L (P = 0.02). However, all the patients' platelet counts returned to near baseline values after the first course. Patients required a median of three courses to achieve stable platelet counts near the normal range. In 4 patients (57%), administration of thiotepa was discontinued because of a stable normal platelet count after a median of 7.5 courses; 1 patient was still receiving treatment at last follow-up (18 courses) and 2 patients stopped receiving treatment after their disease progressed to the blastic phase. Toxicity was mostly hematologic, with neutropenia (< or = 1 x 10(9)/L) occurring during 5 of the 64 courses (8%) administered but only 1 patient's course was complicated by fever. CONCLUSIONS: The authors conclude that thiotepa is useful in controlling thrombocythemia in CML patients who have elevated platelet counts despite having adequate WBC counts.

Adult↗
PubMed2002

Cytochrome P450 isozymes 3A4 and 2B6 are involved in the in vitro human metabolism of thiotepa to TEPA.

PURPOSE: To establish the cytochrome P450 (CYP) isozymes involved in the metabolism of the alkylating agent, thiotepa, to the pharmacologically active metabolite, TEPA. METHODS: In vitro chemical inhibition studies were conducted by incubating thiotepa and pooled human hepatic microsomes in the presence of known inhibitors to CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. Studies were also performed with cloned, expressed CYP3A4, CYP2A6, CYP2E1 and CYP2B6 microsomes, and anti-CYP2B6 monoclonal antibody. RESULTS: Known CYP3A4 inhibitors reduced TEPA production. Inhibition with CYP2E1 inhibitors was inconsistent. All other inhibitors produced little or no change in TEPA formation. Cloned, expressed CYP2B6 and CYP3A4 microsomes catalyzed TEPA formation, whereas CYP2A6 and CYP2E1 did not. Incubation of thiotepa with anti-CYP2B6 antibody and cloned, expressed CYP2B6 microsomes resulted in reductions in the formation of TEPA, but no change in TEPA formation occurred in human liver microsomes. CONCLUSIONS: Thiotepa is metabolized in human liver microsomes by CYP3A4 (major) and CYP2B6 (minor). There is a potential for CYP-mediated drug interactions with thiotepa. Pharmacokinetic variability of thiotepa may be related to expression of hepatic CYP isozymes.

Antibodies↗
PubMed1994

Clastogenic action of thiotepa on bone marrow cells of the Armenian hamster.

Thiotepa (TT) induced chromosomal aberrations in the bone marrow cells of the Armenian hamster, Cricetulus migratorius, in a dose-dependent manner. The maximal clastogenic action was observed 24 h after treatment with thiotepa. Male and female Armenian hamsters were similarly sensitive to the clastogenic action of thiotepa. The lowest effective concentration of thiotepa for Armenian hamsters was 2.5 mg/kg b.w. (6.1% of the LD50). The results obtained and analysis of the literature data have shown that Armenian hamsters are much more resistant to the clastogenic action of thiotepa than various other species of rodent. This resistance is not due to the metabolic activation rates of chemical mutagen in the liver of Armenian hamsters, since thiotepa is a direct-acting clastogen.

Animals↗
PubMed1990

Bacillus Calmette-Guerin versus doxorubicin versus thiotepa: a randomized prospective study in 202 patients with superficial bladder cancer.

We report the second interim analysis of data from a randomized prospective trial comparing the prophylactic effect of 15 courses of 50 mg. doxorubicin, 50 mg. thiotepa or 150 mg. bacillus Calmette-Guerin instilled intravesically against recurrences and progression of superficial transitional cell bladder cancer. Of 202 enrolled patients 176 currently are evaluable with a mean follow-up of 3 years (range 3 to 97 months). The number of patients with recurrences was significantly lower in the bacillus Calmette-Guerin arm (9 of 67) compared to the doxorubicin (23 of 53, p equals 0.002) and thiotepa (20 of 56, p equals 0.003) arms. The over-all recurrence index per 100 patient-months also was lower for the bacillus Calmette-Guerin versus the thiotepa and doxorubicin groups (0.53 versus 1.55 and 1.7, respectively). Bacillus Calmette-Guerin also was superior in preventing recurrences and progression of high risk tumors, that is stage T1, grade 3 or multiple growths, associated or not with carcinoma in situ. In the stage T1 category 19 of 32 (60%) tumors recurred under treatment with doxorubicin, 11 of 33 (33%) with thiotepa and 6 of 49 (12%) with bacillus Calmette-Guerin. Toxicity to intravesical bacillus Calmette-Guerin was higher compared to the other drugs but it was not limiting: bladder irritability and malaise occurred in 42% of the patients, granulomatous cystitis in 16.4% and bladder contraction in 1.4% (1 of 64). The latter complication occurred in a patient whose stage T1m grade 2 tumors had recurred 3 times, who underwent 3 transurethral bladder resections within 15 months and who had received thiotepa for 4 months after having been removed from the study 11 months after entry. Three patients in the doxorubicin group (5.6%) underwent radical cystectomy for local urothelial progression. One patient (1.8%) in the same group died of distant progression. Our preliminary results suggest that at the dose, periodicity and duration used in the study bacillus Calmette-Guerin is significantly superior to the chemotherapeutic agents doxorubicin and thiotepa for the prophylaxis of recurrence and retardation of progression in superficial transitional cell bladder tumors.

Administration, Intravesical↗
PubMed1998

Comparison of mutant frequencies and types of mutations induced by thiotepa in the endogenous Hprt gene and transgenic lacI gene of Big Blue rats.

The utility of the lacI transgene of Big Blue rats as a reporter of in vivo mutation was evaluated by comparing the frequency and types of mutations induced by thiotepa in the transgene and the endogenous Hprt gene. Transgenic rats were given i.p. injections of 1.4 mg/kg of thiotepa three times per week over a period of 4 weeks (a total dose of 16.8 mg/kg); 1 week after the last injection, mutation assays were performed on spleen lymphocytes isolated from the animals. Thiotepa treatment increased the lacI mutant frequency from 34.8 +/- 4.1 x 10(-6) in control animals to 140.9 +/- 64.8 x 10(-6) (p = 0.0020) and the Hprt mutant frequency from 3.5 +/- 1.5 x 10(-6) to 41.1 +/- 23.2 x 10(-6) (p = 0.0028). Sequence analysis of lacI mutant DNA and Hprt mutant cDNA produced similar overall mutation patterns: G:C-->T:A transversion was the most common base pair substitution (32% of independent mutations in the lacI gene and 28% of Hprt mutations), and deletions and insertions accounted for 34% of mutations in the lacI gene and 28% in the Hprt gene. The majority of thiotepa-induced base pair substitutions in the Hprt gene occurred with the mutated purine on the non-transcribed DNA strand, while no strand-related bias was found for mutations in the lacI gene. Substitutions at G:C base pairs in the lacI gene, but not in the Hprt gene, were found disproportionately in CpG sites. In addition, multiplex polymerase chain reaction analysis of genomic DNA from the Hprt mutants indicated that 34% had relatively large deletions; none of these deletions was detected by the cDNA analysis. The results indicate that the frequency of thiotepa-induced mutants in Big Blue rats was 2.8-fold greater in the lacI gene than in the Hprt gene. Although the Hprt gene recovered a fraction of large deletions not found among the lacI mutants, the effects of transcription-coupled DNA repair in the Hprt gene and the targeting of base pair substitutions to G:C base pairs in CpG sites may have contributed to the higher mutant frequencies induced by thiotepa in the lacI transgene compared with the Hprt gene.

Animals↗
PubMed2001

A mechanism-based pharmacokinetic model for the cytochrome P450 drug-drug interaction between cyclophosphamide and thioTEPA and the autoinduction of cyclophosphamide.

Cyclophosphamide (CP) is widely used in high-dose chemotherapy regimens in combination with thioTEPA. CP is a prodrug and is activated by cytochrome P450 to 4-hydroxycyclophosphamide (HCP) which yields the final cytotoxic metabolite phosphoramide mustard (PM). The metabolism of CP into HCP exhibits autoinduction but is inhibited by thioTEPA. The aim of this study was to develop a population pharmacokinetic model for the bioactivation route of CP incorporating the phenomena of both autoinduction and the drug-drug interaction between CP and thioTEPA. Plasma samples were collected from 34 patients who received high-dose CP, thioTEPA and carboplatin in short infusions during 4 consecutive days. Elimination of CP was described by a noninducible route and an inducible route leading to HCP. The latter route was mediated by a hypothetical amount of enzyme. Autoinduction leads to a zero-order increase in amount of this enzyme during treatment. Inhibition by thioTEPA was modeled as a reversible, competitive, concentration-dependent inhibition. PM pharmacokinetics were described by first-order formation from HCP and first-order elimination. The final models for CP, HCP, and PM provided an adequate fit of the experimental data. The volume of distribution, noninducible and initial inducible clearances of CP were 31.0 L, 1.58 L/hr and 4.76 L/hr, respectively. The enzyme amount increased with a zero-order rate constant of 0.041 amount * hr-1. After each thioTEPA infusion, however, approximately 80% of the enzyme was inhibited. This inhibition was reversible with a half-life of 6.5 hr. The formation and elimination rate constants of PM were 1.58 and 0.338 hr-1, respectively. The developed model enabled the assessment of the complex pharmacokinetics of CP in combination with thio TEPA. This model provided an adequate description of enzyme induction and inhibition and can be used for treatment optimization in this combination.

Adolescent↗
PubMed1998

Effects of single, short-term exposures of human retinal pigment epithelial cells to thiotepa or 5-fluorouracil: implications for the treatment of proliferative vitreoretinopathy.

AIM: To investigate the effects of single, short-term (5 or 30 minutes) exposures to thiotepa or 5-fluorouracil (5-FU) on collagen lattice contraction and retinal pigment epithelial (RPE) cell proliferation. METHODS: For collagen contraction studies, RPE cells seeded into free floating type I collagen lattices were exposed to single 5 or 30 minute treatments with thiotepa (0.06-4 mg/ml), or 5-FU (0.25-25 mg/ml), or phosphate buffered saline alone as a control. For proliferation studies, RPE cell monolayers were similarly exposed to these agents. The degree of contraction, effects on cell number, and viability were determined up to 14 days after treatment. RESULTS: Contraction of collagen lattices containing RPE cells and proliferation of RPE cells were significantly inhibited (p < 0.05) by thiotepa and 5-FU at concentrations above 0.06 mg/ml and 0.25 mg/ml respectively (for both 5 and 30 minute treatments), compared with controls. Cell death did not occur except for exposure of the RPE cells in collagen lattices to the highest concentration of thiotepa (4 mg/ml). CONCLUSION: It was concluded that single 5 or 30 minute exposures to thiotepa or 5-FU significantly inhibited collagen contraction and the proliferation of RPE cells. These findings suggest that short, single, non-toxic exposures to thiotepa or 5-FU which can be reproduced clinically may be useful in the modulation of proliferative vitreoretinopathy.

Alkylating Agents↗
PubMed1996

Increased resistance to N,N',N"-triethylenethiophosphoramide (thiotepa) in cells expressing the Escherichia coli formamidopyrimidine-DNA glycosylase.

Thiotepa (N,N',N'-triethylenethiophosphoramide) is an alkylating agent used in cancer chemotherapy. A reaction pathway by which thiotepa alkylates purified DNA involves hydrolysis to aziridine, which forms N7-aminoethyl guanine and aminoethyl adenine. These lesions are repaired in Escherichia coli by the formamidopyrimidine-DNA glycosylase (Fpg) protein. To determine whether such lesions are formed by thiotepa in mammalian cells, we have overexpressed the E. coli Fpg protein in Chinese hamster ovary cells. The transfected cells were more resistant to the lethal and mutagenic effects of thiotepa than the parental cells. The number of replication-blocking lesions formed by thiotepa, measured by quantitative PCR analysis, was lower in the transfected cells. These results show that expression of the Fpg protein increases the cell resistance to thiotepa and suggest that this compound produces ring-opened guanines, which are involved in its cytotoxic action.

Animals↗
PubMed1998

Glutathione-dependent biotransformation of the alkylating drug thiotepa and transport of its metabolite monoglutathionylthiotepa in human MCF-7 breast cancer cells.

In this study, the role of glutathione S-transferase (GST) P1-1, the cellular reduced glutathione (GSH) status, and ATP-dependent efflux pumps in the cellular glutathione-dependent biotransformation of thiotepa and transport of the main metabolite monoglutathionylthiotepa in relation to cytotoxicity was studied in control and GST-P1-1-transfected MCF-7 cell lines. It was demonstrated that an enhanced cellular level of GST-P1-1 leads to an enhanced formation of monoglutathionylthiotepa, which is transported out of the cell into the medium. Monoglutathionylthiotepa was able to reversibly inhibit the activity of purified GST-P1-1, but only at nonphysiological concentrations, indicating that feedback inhibition of GST by its metabolites is not a relevant process in vivo. The GST activity, cellular GSH level, and/or ATP-dependent efflux of monoglutathionylthiotepa were modulated using ethacrynic acid, D,L-buthionine-S,R-sulfoximine, probenecid, and verapamil to understand the interplay between GSTs, glutathione conjugation, and efflux of glutathione conjugates in more detail. Inhibition of the GSH biosynthesis by D,L-buthionine-R,S-sulfoximine, a specific inhibitor of gamma-glutamylcysteine synthetase, significantly reduced the glutathione conjugation of thiotepa and potentiated the cytotoxicity of thiotepa. Pretreatment of cells with ethacrynic acid resulted in decreased formation of monoglutathionylthiotepa as a result of inhibition of GST in the GST-P1-1 transfectant. In addition, the intracellular amount of monoglutathionylthiotepa increased in both of the cell lines on exposure to ethacrynic acid, indicating that transport of the glutathione conjugate was partially inhibited by the glutathione conjugate of ethacrynic acid. Transport activity of monoglutathionylthiotepa could also be inhibited by probenecid and verapamil, inhibitors of organic anion transport, without influencing the biotransformation capacity of the cells. It was demonstrated that inhibition of glutathione conjugate efflux by probenecid and verapamil leads to enhanced cytotoxicity, which indicates that besides thiotepa, monoglutathionylthiotepa is also cytotoxic for the cells. Only enhanced biotransformation and subsequent transport of the glutathione conjugate into the medium (which occurs with the GST-P1-1 transfectant) results in enhanced viability. Therefore, it was concluded that only enhanced biotransformation of thiotepa represents a real detoxification pathway when the resulting conjugate is transported out of the cells. Altogether, the results indicate that it is not the overexpression of GST per se but the interplay between GSH/GST and glutathione conjugate efflux pumps that results in increased resistance to alkylating anticancer drugs such as thiotepa.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

A phase II evaluation of thiotepa in pediatric central nervous system malignancies.

BACKGROUND: Both thiotepa and its active metabolite, tepa, efficiently cross the blood-brain barrier. After intravenous administration, the cerebrospinal fluid concentrations achieved are nearly identical to those in plasma. This provides a strong rationale for testing this agent against brain tumors. METHODS: Sixty pediatric patients with recurrent primary brain tumors were treated on a multiinstitutional Phase II study of intravenous thiotepa at a dose of 65 mg/m2 administered every 3 weeks. This dose is the result of a prior pediatric Phase I trial and is significantly higher than those previously recommended. RESULTS: Three of 13 assessable patients with medulloblastoma had partial responses lasting 22, 25, and 54 weeks. Although no objective responses were observed in 16 assessable patients with malignant gliomas and 14 with brain stem gliomas, 5 of 16 and 4 of 14 patients in these respective strata had prolonged periods of stable disease (SD) lasting from 12 to more than 33 weeks. Nine assessable patients with ependymoma had no objective response, but two had SD, both for more than 33 weeks. Myelosuppression was the principle toxic effect encountered and appeared to be more severe in patients who had received prior craniospinal radiation therapy or nitrosourea therapy. CONCLUSIONS: By conventional Phase II criteria, thiotepa appears to have activity in medulloblastoma. Based on several patients with prolonged SD, it also may possess some limited activity in brain stem and malignant gliomas. The steep in vitro dose-response curve of thiotepa and the long durations of response or SD observed with the dose reported here suggest that moderate-dose to high-dose thiotepa with cytokine support or autologous bone marrow rescue may be associated with an improved response rate to this agent.

Adolescent↗
PubMed1979

Acute metabolic effects of nitrogen mustard and thiotepa on rabbit articular cartilage and synovium.

Metabolic alterations in immature rabbit joint tissue were examined following in vitro and in vivo exposure to the alkylating agents Thiotepa and nitrogen mustard. Brief exposure in vitro to either agent resulted in marked suppression of incorporation of radiolabeled precursors of protein, RNA, and glycosaminoglycan synthesis in articular cartilage, which was partially reversible after Thiotepa exposure. In vivo, nitrogen mustard has little effect on synovium and transient inhibitory effects on cartilage vital processes, whereas Thiotepa caused a prolonged inhibition of synovial metabolism with little effect on cartilage. Autoradiographic localization of labeled agents indicated that synovial tissue and cartilage were readily penetrated by nitrogen mustard, but only a few synovial lining cells and superficial chondrocytes were labeled with 35S-Thiotepa. Furthermore, trypsin significantly reduced labeling of cartilage with 14C-nitrogen mustard. These data suggest that alkylating agents differentially affect metabolic processes in joint tissues in vivo and that with Thiotepa, this interference occurs primarily in the synovium. The degree of interference is apparently dependent upon the time of exposure to the agents and the relative DNA-RNA synthetic activity of the joint tissue.

Animals↗
PubMed1998

A phase II study of intraperitoneal cisplatin and thiotepa in residual ovarian carcinoma: a Gynecologic Oncology Group study.

OBJECTIVE: Patients with advanced epithelial ovarian cancer treated with salvage therapy using new combinations of systemic chemotherapy, radiation therapy, and systemic immunotherapy have had limited success. Since the most common site of relapse or failure to conventional systemic chemotherapy has been the peritoneal cavity, intraperitoneal (IP) chemotherapy was selected to treat small-volume residual disease. METHODS: Sixty-five patients were entered on a protocol using intraperitoneal cisplatin and thiotepa following a response to intravenous cisplatin-based chemotherapy. Patients had surgically documented residual disease (0.5 cm or less maximum tumor diameter) at completion of preprotocol surgery and had no clinical, radiologic, or histologic evidence of extraperitoneal disease. Cisplatin (100 mg/m2) and thiotepa 30 mg/m2 was delivered intraperitoneally every 4 weeks for a maximum of six cycles. The dose of thiotepa was reduced to 12 mg/m2 due to unexpected severe myelosuppression. RESULTS: Of the 52 evaluable patients, grade 4 neutropenia, thrombocytopenia, neurotoxicity, and nephrotoxicity were observed in 31, 19, 13, and 6% of patients, respectively. For all evaluable patients, the complete response rate was 19% and the partial response rate was 2% for a total response rate of 21%. Of 16 patients who had a reassessment laparotomy, 10 patients achieved a surgically documented complete response and 1 patient had a partial response. Four patients are still in response for 67+, 70+, 70+, and 73+ months after third-look surgery. Three patients who did not undergo third-look surgery after chemotherapy are alive and clinically free of disease at 49+, 69+, and 85+ months. CONCLUSION: Thiotepa, when used with cisplatin for IP salvage therapy in patients with advanced or recurrent ovarian cancer, may produce significant myelosuppression and doses must be adjusted accordingly. In cisplatin-sensitive patients with small-volume residual ovarian cancer, IP cisplatin and thiotepa appears to have activity. Determining the utility of this approach will require a randomized trial.

Adult↗
PubMed1987

Influence of the tissue distribution of ThioTEPA and its metabolite, TEPA, on the response of murine colon tumours.

Disposition studies in the same animals as those used for assessment of antitumor and toxic effects could increase understanding of the variation in response to cytotoxic drugs. Tissue and plasma levels of ThioTEPA and triethylenephosphoramide (TEPA) were measured to see if any correlation existed between them and the effects of the drug on a series of mouse colon tumours (MAC). The tumour panel included an ascitic form (MAC 15A), an anaplastic (MAC 13) and a well-differentiated (MAC 26) solid tumour, all grown subcutaneously. The maximum tolerated dose of ThioTEPA was 20 mg kg-1 in females bearing MAC 13 and 15 mg kg-1 in males having MAC 15A or 26. The diverse growth characteristics of the tumour cell lines necessitated the use of different methods for assessment of response. After administration of the maximum tolerated dose, the greatest response was observed in MAC 26, in which a growth delay of 15 days-twice the doubling time of the tumour volume-occurred. ThioTEPA produced 58% inhibition of MAC 13 tumour weight, but MAC 15A was unresponsive. One hour after intraperitoneal administration of Thio-TEPA (20 mg kg-1), ratios of tissue to plasma concentration were 1.13, 0.87 and 1.17 in tumours and 0.80, 0.75 and 0.73 in spleens of mice bearing MAC 13, 15A and 26 respectively. These data show greater accumulation of drug in neoplastic than in normal tissues. The pattern of distribution of the metabolite was similar, but there was a lesser degree of tissue accumulation than by the drug. Concentrations of drug and metabolite in neoplastic tissues related to their protein content were 116.0, 126.3 and 183.3 micrograms ThioTEPA/g and 57.5, 83.1 and 78.6 micrograms TEPA/g in MAC 13, 15A and 26 respectively. Combination of these chemosensitivity and pharmacokinetic data indicates that differences in response of these tumours to ThioTEPA cannot be explained by the availability of the drug and metabolite. The therapeutic effects of ThioTEPA cannot be predicted purely from a knowledge of drug and metabolite disposition.

Adenocarcinoma↗
PubMed1990

Phase I and pharmacokinetic study of intraperitoneal thioTEPA in patients with ovarian cancer.

A total of 15 patients with residual ovarian cancer confined to the peritoneal cavity after first-line systemic chemotherapy were treated with triethylene-thiophosphoramide (thioTEPA) in a phase I study. A total of 50 courses of thioTEPA were given intraperitoneally in doses ranging from 30 to 80 mg/m2. The dose limiting toxicity was myelosuppression, which occurred at 80 mg/m2 and was frequently prolonged. Short-lived nausea and vomiting was easily controlled, and there was no local toxicity. Three patients remain free of disease progression at 6, 6 and 12 months. ThioTEPA concentrations were measured by gas chromatography. Peritoneal fluid concentrations declined rapidly in a first-order fashion, with a half-life of 0.96 +/- 0.1 h. A mean of 93% of the drug was absorbed during the 4-h dwell time. Peak plasma levels were achieved 30-60 min after drug instillation and were substantially lower than corresponding peritoneal levels. A pharmacokinetic advantage for intraperitoneal delivery was detected for peak drug concentration (24.9 +/- 8.5) and AUC (9.2 +/- 4.8). Based on this study, the recommended dose for intraperitoneal thioTEPA is 60 mg/m2 every 3-4 weeks. However, the rapid absorption of this drug from the peritoneum, secondary to thioTEPA's small molecular weight and lipophilic nature, suggests that it has only a limited role in intraperitoneal therapy.

Adult↗