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DICP : the Annals of Pharmacotherapy Feb 1991Altretamine is a National Cancer Institute-designated group C antineoplastic agent used in the treatment of advanced ovarian cancer. Altretamine is a highly... (Comparative Study)
Comparative Study Review
Altretamine is a National Cancer Institute-designated group C antineoplastic agent used in the treatment of advanced ovarian cancer. Altretamine is a highly lipid-soluble drug available only for oral administration as a capsule. The drug is activated through metabolic oxidation to intermediate methylol derivatives and formaldehyde. It is unclear which metabolite is the major species responsible for cytotoxicity or the primary mechanism of cytotoxicity. As a single agent in the treatment of ovarian cancer, altretamine demonstrates a response rate similar to other active agents in this disease (21-39 percent). The major utility of altretamine is in combination with other agents such as cyclophosphamide, doxorubicin, fluorouracil, melphalan, and cisplatin. However, few randomized trials have evaluated the contribution of altretamine in these multiagent combinations. Dose-limiting toxicities include gastrointestinal (nausea, vomiting, anorexia), hematologic, and neurotoxic (peripheral neurotoxicity). The therapeutic role of altretamine is limited because of a toxicity profile similar to that of cisplatin, one of the more active agents in ovarian cancer. Its use should be reserved for patients who are not candidates for more standard platinum-based regimens.
Topics: Altretamine; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Drug Interactions; Female; Fluorouracil; Humans; Lung Neoplasms; Methotrexate; Ovarian Neoplasms
PubMed: 1905441
DOI: 10.1177/106002809102500209 -
Drugs Jun 1995Altretamine (hexamethylmelamine) is a cytotoxic antineoplastic agent which appears to require metabolic activation. Metabolic intermediates may act as alkylating agents;... (Review)
Review
Altretamine (hexamethylmelamine) is a cytotoxic antineoplastic agent which appears to require metabolic activation. Metabolic intermediates may act as alkylating agents; however, altretamine is not directly cross-resistant with classical alkylating agents. Objective response rates to orally administered altretamine as salvage therapy in patients with advanced ovarian cancer were 0 to 33%, with disease stabilisation in a further 8 to 78% of patients. Response rates appear to be higher in patients who have responded to previous alkylating agent or cisplatin-based therapy. There is some evidence that addition of altretamine to platinum-based combination regimens used for induction therapy of advanced ovarian cancer may improve long term survival, particularly in patients with limited residual disease. Although altretamine displays some activity in small cell lung cancer, it is unlikely to have any clinical role in the management of non-ovarian cancer. Altretamine appears to be relatively well tolerated, with gastrointestinal, neurological and haematological toxicities being the main dose-limiting adverse effects. However, assessment of accurate incidence rates for these effects is complicated by the use of altretamine with cisplatin. On the basis of the emerging body of clinical evidence, altretamine appears to have a limited role in the treatment of persistent or recurrent advanced ovarian cancer, primarily in patients who are potentially platinum sensitive yet intolerant of platinum analogues. Additionally, altretamine may be added to platinum-based regimens for induction therapy of advanced ovarian cancer. At the doses currently recommended, altretamine offers a reasonably well tolerated regimen that can be administered orally and is suitable for use on an outpatient basis.
Topics: Altretamine; Antineoplastic Agents; Female; Humans; Lung Neoplasms; Neoplasms; Ovarian Neoplasms; Salvage Therapy
PubMed: 7641606
DOI: 10.2165/00003495-199549060-00007 -
Clinical Pharmacokinetics Jun 1995Altretamine (hexamethylmelamine) is an antitumour drug with demonstrated antitumour activity in refractory ovarian cancer. Due to its poor water solubility, the drug has... (Review)
Review
Altretamine (hexamethylmelamine) is an antitumour drug with demonstrated antitumour activity in refractory ovarian cancer. Due to its poor water solubility, the drug has been given by the oral route. In all animal species, including humans, altretamine undergoes oxidative N-demethylation with the formation of hydroxymethyl derivatives as intermediates. Hydroxymethylmelamines are believed to be responsible for the cytotoxic and antitumour activity of the drug. The inter-hand intrapatient variability of the bioavailability of altretamine after oral administration represents an important drawback for effective clinical use of this drug. The variability appears to be mostly related to the first-pass effect and therefore may be overcome by intravenous administration of the drug. Although attempts to administer the drug intravenously have not been successful in the past, some investigations on the use of the new parental formulation of altretamine are in progress.
Topics: Administration, Oral; Altretamine; Animals; Biological Availability; Dose-Response Relationship, Drug; Humans; Infusions, Parenteral; Injections, Intravenous; Molecular Structure
PubMed: 7656502
DOI: 10.2165/00003088-199528060-00002 -
Journal of Biomolecular Structure &... Jun 2023Insights into drug-DNA interactions have importance in medicinal chemistry as it has a major role in the evolution of new therapeutic drugs. Therefore, binding studies...
Insights into drug-DNA interactions have importance in medicinal chemistry as it has a major role in the evolution of new therapeutic drugs. Therefore, binding studies of small molecules with DNA are of significant interest. Spectroscopy, coupled with measurements of viscosity and molecular docking studies were employed to obtain mechanistic insights into the binding of altretamine with calf thymus DNA (CT-DNA). The UV-visible spectroscopic measurements study confirmed altretamine-CT-DNA complex formation with affinity constant ([15.68 ± 0.04] × 10 M), a value associated with groove binding phenomenon. The associated thermodynamic signatures suggest enthalpically driven interactions. The values of standard molar free energy change () -(23.93 ± 0.23) kJ mol, enthalpy change () -(50.84 ± 0.19) kJ mol and entropy change () -(90.29 ± 0.12) JK mol indicate the binding is thermodynamically favorable and an important role of the hydrogen bonds and Van der Waals interactions in the binding of altretamine with CT-DNA. Circular dichroism spectroscopy indicated insignificant conformational changes in the DNA backbone upon interaction with altretamine suggesting no distortion and/or unstacking of the base pairs in the DNA helix. UV-melting study suggested that the thermal stability of the DNA backbone is not affected by the binding of the drug. Competitive displacement assays with ethidium bromide, Hoechst-33258 and DAPI established the binding of altretamine with CT-DNA in the minor groove. The mode of binding was further confirmed by viscosity and molecular docking studies. Molecular docking further ascertained binding of altretamine in the minor groove of the CT-DNA, preferably with the A-T rich sequences.[Formula: see text]HighlightsAltretamine binds CT-DNA which is enthalpically driven with K of the order of 10Insignificant conformational change is observed due to DNA-altretamine complexationAltretamine binds favorably with A-T rich sequences in the minor groove of CT-DNAMechanistic insights obtained based on thermodynamic signaturesCommunicated by Ramaswamy H. Sarma.
Topics: Altretamine; Molecular Docking Simulation; DNA; Ethidium; Thermodynamics; Circular Dichroism; Spectrometry, Fluorescence; Spectrophotometry, Ultraviolet; Viscosity
PubMed: 35343872
DOI: 10.1080/07391102.2022.2054472 -
Cancer Treatment Reviews Mar 1991
Clinical Trial Randomized Controlled Trial Review
Topics: Altretamine; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Cyclophosphamide; Female; Fluorouracil; Humans; Methotrexate; National Institutes of Health (U.S.); Neoplasm Staging; Ovarian Neoplasms; United States
PubMed: 1904307
DOI: 10.1016/0305-7372(91)90022-r -
Cancer Treatment Reviews Mar 1991
Review
Topics: Altretamine; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Small Cell; Humans; Lung Neoplasms
PubMed: 1646071
DOI: 10.1016/0305-7372(91)90028-x -
International Journal of Biological... Oct 2019Binding of anticancer drug altretamine with bovine serum albumin (BSA) and its inhibitory effect on fibrillation of the protein has been studied by using a combination...
Binding of anticancer drug altretamine with bovine serum albumin (BSA) and its inhibitory effect on fibrillation of the protein has been studied by using a combination of spectroscopic and calorimetric methods. Altretamine is observed to bind with BSA with a moderate binding affinity of the order of 10, which is weakly temperature dependent. Circular dichroism, fluorescence spectroscopic and dynamic light scattering methods have been employed to monitor the conformational change in the protein. Time correlated single photon counting measurements have confirmed ground state complexation of the drug with the protein. Docking studies have led to identification of binding sites on BSA at site III in domain IB. Thioflavin T (ThT) fluorescence emission has been used as a tool to monitor the formation of fibrils/aggregates in BSA. It is observed that anticancer drug altretamine can also act as an inhibitor of fibrillation in BSA and hence can be useful in the treatment of neuro-degenerative diseases. Differential scanning calorimetry has been employed to study the thermal transitions of BSA at different stages of the fibrillation process with and without altretamine to obtain insights into the extent of stabilisation provided by the drug to the protein in native, nucleation/elongation and matured state in the fibrillation process.
Topics: Altretamine; Animals; Antineoplastic Agents; Cattle; Molecular Docking Simulation; Protein Conformation; Protein Multimerization; Serum Albumin, Bovine; Temperature
PubMed: 31323265
DOI: 10.1016/j.ijbiomac.2019.07.093 -
Gynecologic Oncology Feb 2003To evaluate the activity of oral Altretamine in women with epithelial ovarian carcinoma who responded (PR or CR) to first line chemotherapy but relapsed within 6 months.... (Clinical Trial)
Clinical Trial
OBJECTIVE
To evaluate the activity of oral Altretamine in women with epithelial ovarian carcinoma who responded (PR or CR) to first line chemotherapy but relapsed within 6 months. The protocol was later amended to include patients with relapse within 12 months.
METHODS
A multicentric phase II trial. The patients had to have measurable disease. No more than one prior chemotherapy regiment was allowed. The patients were treated with 260 mg/m(2)/day of Altretamine in four divided doses for 2 weeks, repeated every 4 weeks. The response was evaluated after every two courses.
RESULTS
Thirty-one eligible patients were treated with a median of 3 courses of Altretamine (range 1-12). Hematological toxicity was minimal. Gastrointestinal toxicity was common. Response evaluation was possible for 26 patients. Three patients (9.7% intent-to-treat) achieved a partial response. Eight patients had stable disease, and 15 patients had progressive disease after two treatment courses. The median time to progression was 10 weeks (range, 5-51 weeks). Medial survival was 34 weeks (range, 7-112+).
CONCLUSION
Altretamine should not be chosen as standard treatment in patients with platinum-resistant recurrent ovarian cancer. However, Altretamine represents a useful alternative in patients who prefer oral treatment or when socioeconomic considerations are an important issue.
Topics: Administration, Oral; Aged; Altretamine; Antineoplastic Agents, Alkylating; Drug Resistance, Neoplasm; Female; Humans; Middle Aged; Organoplatinum Compounds; Ovarian Neoplasms
PubMed: 12586589
DOI: 10.1016/s0090-8258(02)00103-8 -
Pharmaceutics Jan 2023In the current study, the combined anti-tumor efficacy of bioactive hydroxyapatite nano- particles (HA-NPs) loaded with altretamine (ALT) was evaluated. The well-known...
In the current study, the combined anti-tumor efficacy of bioactive hydroxyapatite nano- particles (HA-NPs) loaded with altretamine (ALT) was evaluated. The well-known fact that HA has great biological compatibility was confirmed through the findings of the hemolytic experiments and a maximum IC value seen in the MTT testing. The preparation of HA-NPs was performed using the chemical precipitation process. An in vitro release investigation was conducted, and the results demonstrated the sustained drug release of the altretamine-loaded hydroxyapatite nanoparticles (ALT-HA-NPs). Studies using the JURKAT E6.1 cell lines MTT assay, and cell uptake, as well as in vivo pharmacokinetic tests using Wistar rats demonstrated that the ALT-HA-NPs were easily absorbed by the cells. A putative synergism between the action of the Ca ions and the anticancer drug obtained from the carrier was indicated by the fact that the ALT-HA-NPs displayed cytotoxicity comparable to the free ALT at 1/10th of the ALT concentration. It has been suggested that a rise in intracellular Ca ions causes cells to undergo apoptosis. Ehrlich's ascites model in Balb/c mice showed comparable synergistic efficacy in a tumor regression trial. While the ALT-HA-NPs were able to shrink the tumor size by six times, the free ALT was only able to reduce the tumor volume by half.
PubMed: 36678930
DOI: 10.3390/pharmaceutics15010302