Pharmacokinetic study of solid-lipid-nanoparticles of altretamine complexed epichlorohydrin-ß-cyclodextrin for enhanced solubility and oral bioavailability.

Altretamine is a synthetic drug approved for treatment of ovarian cancer. The only drawback with its formulation is poor aqueous solubility and low oral bioavailability. In the present work an attempt has been made to prepare inclusion complex of altretamine with epichlorohydrin beta cyclodextrin. The complexes were prepared by kneading, co-evaporation and freeze-drying method and were confirmed by FTIR, XRD, DSC, drug content and dissolution study. Kneaded complex possess maximum solubilizing efficiency of 82.63 in 25mM Epi-ß-CD solution. SLNs of pure altretamine and ALT complexed with Epi-ß-CD were prepared by modified emulsification-ultrasonication method. The particle size and zeta potential was found to be 151.5nm and -21.3mV. The drug release pattern of SLNs was bi-phasic in nature; with an initial burst release followed by sustained drug release. Pharmacokinetic study showed that the average Cmax was found to be 0.94µg/ml, which was 2.47 times higher as compared to the pure drug. The AUCt for SLNs was 150minµgh/ml and 54minµgh/ml for pure ALT suspension which proved that the SLNs exhibited greater absorption compared to the pure drug. Thus, smaller particle size, higher entrapment efficiency and enhanced aqueous solubility led to improvement in oral bioavailability of ALT.

Liposomes incorporating sodium deoxycholate for hexamethylmelamine (HMM) oral delivery: development, characterization, and in vivo evaluation.

Liposomes incorporating sodium deoxycholate (NaDC) were prepared by the method of reverse phase evaporation and used for drug delivery by the oral route. Hexamethylmelamine (HMM), an anti-tumor agent, was chosen as a model drug and encapsulated into liposomes incorporating NaDC (NaDC-Lip). Several properties of NaDC-Lip containing HMM (HMM NaDC-Lip), such as particle size, entrapment efficiency, pinacyanol chloride (PIN) spectral characteristics with various molar ratio of NaDC/PC, as well as the vesicle stability measurements with calcein were evaluated. In vivo, the area under the plasma concentration-time curve obtained from the pharmacokinetics study of HMM NaDC-Lip was found to be approximately 9.76- and 1.21-fold higher than that of HMM solution and HMM Lip, respectively, indicating that NaDC-Lip can be used as a potential carrier for oral drug administration.

Synergy of irofulven in combination with other DNA damaging agents: synergistic interaction with altretamine, alkylating, and platinum-derived agents in the MV522 lung tumor model.

PURPOSE: Irofulven (MGI 114, NSC 683863) is a semisynthetic derivative of illudin S, a natural product present in the Omphalotus illudins (Jack O'Lantern) mushroom. This novel agent produces DNA damage, that in contrast to other agents, is predominately ignored by the global genome repair pathway of the nucleotide excision repair (NER)(2) system. The aim of this study was to determine the antitumor activity of irofulven when administered in combination with 44 different DNA damaging agents, whose damage is in general detected and repaired by the genome repair pathway. METHODS: The human lung carcinoma MV522 cell line and its corresponding xenograft model were used to evaluate the activity of irofulven in combination with different DNA damaging agents. RESULTS: Two main classes of DNA damaging agents, platinum-derived agents, and select bifunctional alkylating agents, demonstrated in vivo synergistic or super-additive interaction with irofulven. DNA helicase inhibiting agents also demonstrated synergy in vitro, but an enhanced interaction with irofulven could not be demonstrated in vivo. There was no detectable synergistic activity between irofulven and agents capable of inducing DNA cleavage or intercalating into DNA. CONCLUSION: These results indicate that the antitumor activity of irofulven is enhanced when combined with platinum-derived agents, altretamine, and select alkylating agents such as melphalan or chlorambucil. A common factor between these agents appears to be the production of intrastrand DNA crosslinks. The synergistic interaction between irofulven and other agents may stem from the nucleotide excision repair system being selectively overwhelmed at two distinct points in the pathway, resulting in prolonged stalling of transcription forks, and subsequent initiation of apoptosis.

Pretreatment CA-125 and risk of relapse in advanced ovarian cancer.

PURPOSE: A previous report suggested the nadir serum CA-125 level within the group of patients with ovarian cancer who achieved normalization of CA-125 accurately defined the risk of relapse. Using similar CA-125 subgroups, we sought to determine if the baseline CA-125 level before initiation of maintenance chemotherapy in women achieving a clinically-defined complete response to primary chemotherapy would be of prognostic value. PATIENTS AND METHODS: Patients included in this retrospective analysis had been treated on one of two previously reported trials of maintenance chemotherapy (three v 12-monthly cycles of paclitaxel; oral altretamine), with a baseline CA-125 level of < or = 35 u/mL. Progression-free survival (PFS) from study entry was analyzed by the Cox regression model. RESULTS: The distribution of premaintenance baseline CA-125 levels for the 384 patients was 58%, 34%, and 8% for values of (A) < or = 10 u/mL, (B) 11 to 20 u/mL, and (C) 21 to 35 u/mL, respectively. The baseline CA-125 was highly statistically significant, either as a categoric variable (P < .001) or as a continuous variable (P < .0001). Median PFS was 24 months, 17 months, and 7 months for groups (A), (B), and (C), respectively. There was no evidence the CA-125 effect differed by trial or treatment in an interaction analysis (P = .70). CONCLUSION: The baseline CA-125 level before initiation of maintenance chemotherapy strongly predicts the risk of subsequent relapse. Patients with premaintenance baseline CA-125 values < or = 10 u/mL have a superior PFS compared with higher levels in the normal CA-125 range.

Recurrent ovarian cancer: how important is it to treat to disease progression?

Ovarian cancer is increasingly recognized as a chronic disease whose treatment is often characterized by administration of multiple, sequential active agents, each of which may or may not be accompanied by a tumor response. Despite the large proportion of patients who relapse and undergo longer-term treatment, the question of optimal treatment duration has not been fully addressed to date. For patients who progress on therapy, the answer is straightforward: they are switched to another active agent, presumably having a different mechanism of action from previous therapies with, ideally, limited overlapping toxicities. However, for patients who remain in partial response or who have stable disease, the answer is less apparent and less clear. The majority of oncologists believe that treatment beyond 6 cycles of a given therapy does not provide any additional benefit to patients. There are some data to support that treatment strategy. However, with the advent of new, less toxic agents, treatment to progression should be further explored. Agents that are potentially well suited for extended treatment intervals may include such properties as absence of cumulative toxicity, non-cross-resistance, positive benefit on quality of life, and convenient schedule. A number of active agents in ovarian cancer (platinum, paclitaxel, topotecan, liposomal doxorubicin, docetaxel, gemcitabine, and etoposide) will be reviewed in the context of what is known about cumulative toxicity, potential adverse effects on patients' quality of life, and evidence addressing the potential benefits of longer-term treatment.

Long-term follow-up of a phase II trial of oral altretamine for consolidation of clinical complete remission in women with stage III epithelial ovarian cancer in the Southwest Oncology Group.

OBJECTIVE: This report provides follow-up progression-free survival (PFS) and median survival data for women who achieved clinical complete remission (cCR) from stage III ovarian cancer after first-line therapy and were treated with altretamine consolidation therapy. METHODS: Patients who enrolled in the SWOG 9326 study from September 1993 to July 1997 were required to have documented cCR from stage III ovarian cancer following front-line platinum-based therapy. Treatment consisted of 6 months of oral altretamine at 260 mg/m(2)/day for 14 consecutive days of a 28-day cycle. RESULTS: Ninety-seven of 112 enrolled patients were evaluable for efficacy. This report presents median 6.2-year follow-up, dating from study registration. Median PFS was 28 (95% CI: 19-43) months. Median PFS for patients with optimal disease was 45 (95% CI: 27-48) months and for patients with suboptimal disease was 17 (95% CI: 12-26) months. Twenty-six of 61 (43%) patients with optimally debulked lesions and 5 of 36 (14%) patients with suboptimally debulked lesions remained disease free. Median survival of patients with optimally debulked disease has not been reached; median survival of patients with suboptimally debulked disease was 39 (95% CI: 19-51) months. No treatment-related adverse events were reported during the follow-up period. CONCLUSIONS: Consolidation therapy with oral altretamine was generally well tolerated and associated with prolonged progression-free and overall survival in the Phase II setting.

Oral altretamine used as salvage therapy in recurrent ovarian cancer.

BACKGROUND: Altretamine has reported efficacy in the treatment of recurrent ovarian cancer following platinum-based therapy. This report presents the cases of two long-term survivors with recurrent ovarian cancer given oral altretamine. CASES: Two patients diagnosed with stage IIIC ovarian cancer underwent optimal cytoreductive surgery. Both women were subsequently treated with platinum-based chemotherapy. One had persistent cancer documented 2 months post therapy, while the other was disease-free for 22 months before recurring. Both received altretamine in a salvage setting. Each of these women achieved a prolonged response to third-line altretamine therapy, and one of whom was disease-free for 4 years and the other remains disease-free over 7 years following initiation of salvage therapy. CONCLUSION: Outpatient-administered oral altretamine can provide a prolonged disease-free interval with minimal toxicity.

Solvent, emulsifier and drug concentration factors in poly(D,L-lactic acid) microspheres containing hexamethylmelamine.

Biodegradable poly(D,L-lactic acid) (PLA) microspheres containing hexamethylmelamine (HMM) were developed for potential use in chemoembolization and intraperitoneal implantation. The emulsion-solvent-evaporation/extraction method was used to prepare 15 formulations with different drug/polymer ratios, solvent compositions and emulsifer concentrations in the continuous aqueous phase. A central composite experimental design was used, with five levels of the three different factors. All formulations resulted in the formation of discrete matrix microspheres containing crystalline drug. The mean particle sizes of the microsphere formulations ranged from 62-348 microm and the effect of the independent variables on microsphere size was satisfactorily predicted using response surface methodology. For theoretical drug loads of 5-40%, efficiency of entrapment ranged from 75-107% and porosities of the microspheres were between 0-6.5%. The rate of drug release from the microspheres depended on drug loading and particle size. Microspheres with 22.5% or greater theoretical drug content released drug rapidly, with almost complete release occurring in 70 h or less. Formulations with drug loading of 5% and 9.57%, however, released drug very slowly, with less than 50% released in 40 days. Release kinetics of narrow sieve cuts of microspheres with high drug load (35.4%) followed square root of time profiles.

A phase I study of paclitaxel and altretamine as second-line therapy to cisplatin regimens for ovarian cancer.

PURPOSE: The efficacy and pharmacokinetics of paclitaxel when combined with altretamine for ovarian cancer were studied. METHODS: A group of 30 patients, whose only chemotherapy was one or more cisplatin-based non-paclitaxel-containing regimens and whose ovarian cancer failed to respond or had relapsed within 6 months of their last platinum regimen, received paclitaxel as a 3-h intravenous infusion and altretamine given orally in four divided doses daily for 14 days repeated every 28 days. Doses were escalated from paclitaxel/altretamine 135/150 mg/m2 to 250/300 mg/m2 in cohorts of three patients. RESULTS: The dose-limiting toxicities at 250/300 mg/m2 were WHO grade 3 myalgias and arthralgias in two patients and grade 3 lethargy, stomach cramps, peripheral neuropathy and vomiting in single patients. Considering all dose levels in cycle 1, 16 patients had grade 3 or 4 neutropenia but there was only one episode of febrile neutropenia. Other grade 3 toxicities were vomiting in four patients, myalgias in three, peripheral neuropathy in two and lethargy in two. Grade 3 alopecia occurred in 23 patients. Three patients achieved a complete response and 12 achieved a partial response for an overall objective response rate of 50%. Responses occurred at all dose levels of 175/150 mg/m2 and higher. The median freedom from progression was 35 weeks, with a median survival of 55 weeks. Altretamine did not alter the pharmacokinetics of paclitaxel and there were no consistent differences in paclitaxel pharmacokinetic parameters or toxicities between course 1 and 2. No dose-response relationships were evident above paclitaxel/altretamine 175/150 mg/m2. CONCLUSION: Paclitaxel and altretamine can be safely combined and with a high response rate in relapsed ovarian cancer, justifying further studies with this combination.

Phase II study of vinorelbine in the treatment of platinum-resistant ovarian carcinoma.

OBJECTIVE: The purpose of this phase II study was to evaluate on an intent-to-treat basis the activity and toxicity of single-agent vinorelbine (VRL) as second-line chemotherapy of patients with platinum-resistant ovarian cancer. Platinum-resistant disease was defined as disease refractory to or relapsing within 12 months after finishing platinum-containing chemotherapy. METHODS: VRL (30 mg/m(2)) was administered intravenously as a bolus injection days 1 and 8 every 21 days. Initially, four courses of VRL were given. Patients with responding or stable disease received four more courses of VRL to a maximum of eight courses. RESULTS: Twenty-eight of 33 eligible patients were considered evaluable for response. The overall response rate was 21% (7/33) (95% CI: 7--35). Median time to progression was 3.1 months and median survival was 10.1 months. Toxicity was generally mild. Leukopenia was the dose-limiting toxicity. CALGB grade III/IV infection was observed in 15/0% of patients. The most important nonhematologic toxicities were nausea and constipation. Grade III/IV nausea was observed in 6/0% and grade III/IV constipation in 3/3% of patients. Peripheral neurotoxicity was only a minor problem with no grade III/IV toxicity. No patients stopped treatment because of toxicity and no toxic death was reported. CONCLUSION: VRL was generally well tolerated, but the activity in platinum-resistant ovarian cancer was only modest, although fully comparable to other second-line treatments. Further studies are required to define the role of VRL in combination chemotherapy for ovarian cancer.

[Combination chemotherapy with hexamethylamine (Hexalen, Altretamine, Hexastat) and sarcolysine in advanced ovarian carcinoma]. / Kombinirovannaia khimioterapiia geksametilmelaminom (Geksalenom, Altretaminom, Geksastatom) i sarkolizinom pri rasprostranennom rake iaichnikov.

Combination chemotherapy with hexamethylmelamine (hexalen, altretamine, hexastat), 100 mg, thrice a day, per os, 14 days (out of a 28-day course) and sarcolysin, 15 mg, per os, during the first 5 days of the course, was received by 24 patients with primary advanced tumors of the ovaries, prior to or after cytoreductive surgery. Total apparent response to chemotherapy among 19 patients of the study group was 47.2%, clinically significant (plus stabilization)--94.5%, without significant untoward side-effects (vomiting--19%; leukopenia degree II-III--33% and thrombocytopenia--19%). The drug proved an active component of combination therapy for advanced ovarian carcinoma.

Comparative study on three chemotherapeutic regimens for the treatment of advanced epithelial ovarian cancer.

To investigate the best first-line chemotherapy regimen for the treatment of advanced epithelial ovarian cancer (AEOC), the efficacy of three chemotherapy regimens for treatment of the patients with AEOC in our hospital during Jan. 1992-Jan. 1999 was retrospectively analyzed. The therapeutic effects were compared with the supplement of Melphalan + Hexamethylme (PAM + HMM), cisplatin + adriamycin + cyclophosphamide or isofamide (PAC) or cisplatin + cyclophosphamide or isofamide (PC), Taxol + cisplatin (TP) combined chemotherapy after cytoreductive surgery. The results showed that the overall effective rate of TP was significantly higher than that of PAM + HMM (P < 0.05); The complete remission rate of TP was significantly higher than that of PAM + HMM and PAC or PC (all P < 0.05); The 2-year survival rate free of tumor of TP was obviously higher than that of PAM + HMM and PAC or PC (all P < 0.05). It was concluded that the therapeutic effect of TP regimen in the treatment of AEOC was better than PAM + HMM and PAC or PC and TP regimen could be recommended currently as the preferred first-line one for the treatment of AEOC.

Paclitaxel, carboplatin, and hexamethyl-melamine (taxchex) as first-line therapy for ovarian cancer.

BACKGROUND: The addition of hexamethylmelamine to therapy with cisplatin, cyclophosphamide, and doxorubicin significantly enhanced outcomes of patients with advanced ovarian cancer. Hexamethylmelamine, also known as altretamine, has potent antineoplastic activity when used as a single agent in patients who have failed to respond to both platinum-based and paclitaxel therapy. We have conducted a pilot study to evaluate the efficacy and safety of adding this drug to the popular ovarian cancer regimen of paclitaxel plus carboplatin. METHODS: Patients with advanced ovarian, fallopian tube, or primary peritoneal cancer (International Federation of Gynecology and Obstetrics stages IIA, IIIC, and IV) were prospectively enrolled to receive six cycles, repeated every 4 weeks, of paclitaxel (150 mg/m2 i.v., day 1), carboplatin (AUC 5.0 i.v., day 1), and hexamethylmelamine (150 mg/m2 p.o., days 2-15). Colony stimulating factors were prohibited. Response and toxicity were monitored by use of Eastern Cooperative Oncology Group criteria. RESULTS: Twenty patients were enrolled, 18 with ovarian cancer, one with fallopian tube cancer, and one with peritoneal cancer; 17 of these patients were evaluable for response and toxicity. At a median follow-up of 6.5 months, 13 of the patients had a complete response (76%), and four had progressive disease. Three of those with a complete response had a recurrence within 1 year of completing treatment. Toxicity was acceptable, with myelosuppression the most severe adverse effect; one patient had grade 3 anemia, one patient had grade 4 thrombocytopenia, and 12 patients had grade 4 neutropenia. Quality of life showed improvement over the course of therapy, particularly in the physical well-being subscale. CONCLUSION: The addition of hexamethylmelamine to paclitaxel and carboplatin is a well-tolerated multidrug combination for women with advanced ovarian cancer that deserves further testing in a phase III study.

Altretamine (hexamethylmelamine) in platinum-resistant and platinum-refractory ovarian cancer: a Gynecologic Oncology Group phase II trial.

OBJECTIVES: In an effort to critically examine the antitumor activity of altretamine (hexamethylmelamine) as salvage therapy of platinum-refractory ovarian cancer, the Gynecologic Oncology Group initiated a Phase II trial of the agent administered in this clinical setting. METHODS: Altretamine was administered at a dose of 260 mg/m2 orally for 14 days in a 28-day course. Treatment was continued until disease progression or unacceptable side effects prevented further therapy. A total of 36 patients (median age: 56.5) were treated on this trial, of whom 33 were evaluable for toxicity and 30 for response. All patients had previously received either cisplatin or carboplatin and paclitaxel. RESULTS: The major side effect was emesis (grade 3-4, 7/33, 21%). The objective response rate was 10% (one complete response, two partial responses). CONCLUSION: We conclude that altretamine has limited activity in platinum-refractory ovarian cancer.

Phase II trial of oral altretamine for relapsed ovarian carcinoma: evaluation of defining response by serum CA125.

PURPOSE: A phase II study was performed of oral altretamine in 71 patients with ovarian carcinoma who entered clinical complete remission with CA125 levels less than 35 U/mL after initial or second-line chemotherapy, and relapsed more than 6 months later. Response was compared between standard and CA125-based criteria. PATIENTS AND METHODS: Altretamine 260 mg/m2 was given in divided doses daily for 14 days per month. Response was evaluated according to European Organization for Research and Treatment of Cancer (EORTC) criteria in 45 of 66 eligible patients. Response was assessed according to precise CA125 criteria in 51 patients based on either a confirmed > or = 50% or > or = 75% decrease in CA125 levels. RESULTS: A combination of domperidone, dexamethasona, and chlorpromazine at night controlled toxicity in most patients, which was mainly nausea (National Cancer Institute criteria grade 2 or 3 in 27), vomiting (grade 2 or 3 in 19, grade 4 in one), and tiredness (grade 2 or 3 in 15). Responses (complete plus partial) were seen in 18 (40%; 95% confidence interval [CI], 25.4% to 54.6%) of those evaluated according to EORTC criteria and in 20 (39%; 95% CI, 25.5% to 52.9%) of those evaluated according to CA125 level. The overall response rate was 26 of 57 (45.6%) and was related to treatment-free interval: 6 to 12 months, 35%; 12 to 24 months, 52%; and greater than 24 months, 67%. The medium duration of response was 8 months. CONCLUSION: Oral altretamine is a useful agent in patients-who relapse after previously responsive ovarian cancer. Response evaluation by a strict CA125 definition gave a similar estimate of the efficacy of altretamine as EORTC criteria.

[Chemotherapy for recurrent ovarian cancer].

The standard treatment for ovarian cancer is cytoreductive surgery followed by platinum-based combination chemotherapy. Although high response rates of this treatment are reported, 40-60% of patients achieving a complete response may relapse. Therefore, second-line chemotherapy is required. Second-line chemotherapy of patients with recurrent ovarian cancer should be based on their sensitivity to first-line chemotherapy and the platina-free interval. Patients who respond to the platina-based chemotherapy still may be sensitive to further platina-based chemotherapy. Patients who do not respond to the platina-based chemotherapy or who have relapses shortly after first-line chemotherapy should be considered clinically resistant to further platina-based chemotherapy. For such patients the chemotherapy regimen should be changed. These regimens include paclitaxel and hexamethylmelamine. The effect of intraperitoneal chemotherapy may depend on the size of the largest residual tumor nodule and the patient's sensitivity to previous chemotherapy.