maytansine and Carcinoma--Squamous-Cell

Some pharmacologic properties of nine antitumor agents from higher plants are described. The agents are vincristine, vinblastine the epiodophyllotoxin derivatives VM-26 and VP-16-213, maytansine, bruceantin, thalicarpine, camptothecin, and lapachol. When sufficient information is available, the agents are discussed with regard to their antitumor activity, mechanism of action, pharmacologic disposition, structure-activity relationships, and toxicity.

Topics: Animals; Antineoplastic Agents, Phytogenic; Aporphines; Camptothecin; Carcinoma, Squamous Cell; Chemical Phenomena; Chemistry; Etoposide; Humans; Leukemia L1210; Leukemia, Experimental; Leukemia, Lymphoid; Maytansine; Melanoma; Naphthoquinones; Nasopharyngeal Neoplasms; Neoplasms; Neoplasms, Experimental; Phenanthrenes; Structure-Activity Relationship; Teniposide; Vinblastine; Vincristine

CD44v6 is a tumor associated antigen abundantly expressed in head and neck squamous cell carcinomas (HNSCC) and in normal squamous epithelium. The immunoconjugate bivatuzumab mertansine (BIWI 1) consists of a highly potent antimicrotubule agent coupled to a monoclonal antibody against CD44v6. The maximum tolerated dose (MTD), safety and efficacy of BIWI 1 administered IV in patients with HNSCC has not been determined. In a clinical phase I trial, adult patients with recurrent or metastatic HNSCC were treated intravenously with BIWI 1. Starting with 25mg/m(2), the dose was escalated in steps of 25mg/m(2) until dose limiting toxicity was observed. Six women and 25 men were included. The MTD was 300 mg/m(2). Twelve patients were treated with at least the MTD. The principal toxic effects were maculopapular rashes, focal blister formation and skin exfoliation. Three patients had partial responses at doses of 200, 275 and 325 mg/m(2). The concept that bivatuzumab can direct mertansine activity to CD44v6 expressing tumors was confirmed. Although CD44v6 was abundantly expressed in all tumors, the response to BIWI 1 was variable. Binding to CD44v6 on skin keratinocytes mediated serious skin toxicity with a fatal outcome in a parallel trial, which led to the termination of the development program of bivatuzumab mertansine and the present study.

Topics: Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Carcinoma, Squamous Cell; Dose-Response Relationship, Drug; Female; Head and Neck Neoplasms; Humans; Hyaluronan Receptors; Immunoconjugates; Infusions, Intravenous; Male; Maximum Tolerated Dose; Maytansine; Middle Aged; Patient Selection; Treatment Outcome

The prodrug bivatuzumab mertansine (BIWI 1) is a novel CD44v6-targeting humanized monoclonal antibody coupled to the toxin mertansine. In a phase I dose escalation trial 31 patients with squamous cell carcinomas of the head and neck were treated with doses of 25-325 mg/m2 as a 30-min infusion. Thirteen patients received a second infusion after 3 weeks. Serial serum samples were collected to determine the pharmacokinetic parameters of the prodrug BIWI 1 and of deconjugated BIWI 1 as well as the occurrence of anti-BIWI 1 antibodies. The maximum tolerated dose was reached at 300 mg/m2 attributable to skin toxicity. No immune response was observed in any patient. For BIWI 1 and deconjugated BIWI 1, clearance values were low and distribution was limited resulting in half-lives of approximately 3-3.5 days and approximately 6-7 days, respectively, for single and repeated dosing after three weeks. Overall, interindividual variability of the pharmacokinetic parameters was low. In general, the pharmacokinetics of both compounds after single and repeated dosing was comparable across the entire dose range and no significant accumulation took place. Over the dose range investigated, a dose proportional increase in the exposure of BIWI 1 and deconjugated BIWI 1 was observed. Dose individualization according to body size (weight or body surface area) was found to be appropriate and is recommended for the novel immunoconjugate.

Topics: Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Carcinoma, Squamous Cell; Female; Glycoproteins; Head and Neck Neoplasms; Humans; Hyaluronan Receptors; Male; Maximum Tolerated Dose; Maytansine; Middle Aged; Prodrugs; Safety

To assess safety, pharmacokinetics, maximum tolerated dose, and preliminary efficacy of bivatuzumab mertansine. Bivatuzumab is a humanized monoclonal antibody directed against CD44v6, which previously seemed to be safe in phase I radioimmunotherapy trials, whereas the conjugated mertansine is a potent maytansine derivative.. Patients with incurable squamous cell carcinoma of the head and neck or esophagus were eligible. Bivatuzumab was given weekly for 3 consecutive weeks by i.v. infusion. One patient was planned to be treated at each dose tier as long as toxicity did not reach grade 2; otherwise, three patients had to be treated until dose-limiting toxicity occurred. Starting dose was 20 mg/m2 and dose was subsequently escalated in steps of 20 mg/m2. Patients without disease progression and not experiencing dose-limiting toxicity were eligible for repeated courses. Blood serum samples were taken throughout the treatment period to determine the pharmacokinetic properties of bivatuzumab mertansine and to assess the human anti-bivatuzumab mertansine antibody response.. Seven patients received a total of 23 weekly doses of bivatuzumab mertansine. One patient at the 100 mg/m2 and one at the 120 mg/m2 level experienced stable disease during treatment phase but also developed grade 1 skin toxicity (desquamation). One of them received a second treatment course. At the highest dose level achieved in this study (140 mg/m2), one patient developed toxic epidermal necrolysis after two infusions and died. Massive apoptosis of skin keratinocytes had occurred, whereas only symptomatic therapy for skin toxicity was available. The risk-benefit assessment of all patients treated in the total phase I program (4 clinical trials, 70 patients) turned out to be negative after consideration of this case of a toxic epidermal necrolysis and the skin-related adverse events observed in the other trials. Therefore, development of the conjugate was discontinued. Interindividual variability in pharmacokinetic variables was low and exposure to BIWI 1 increased proportionally with dose. No anti-bivatuzumab mertansine reactions were observed.. The main toxicity of bivatuzumab mertansine was directed against the skin, most probably due to CD44v6 expression in this tissue. The majority of skin reactions was reversible; however, one fatal drug-related adverse event had occurred. Clinical development was discontinued before reaching maximum tolerated dose.

Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Carcinoma, Squamous Cell; Dose-Response Relationship, Drug; Esophageal Neoplasms; Glycoproteins; Head and Neck Neoplasms; Humans; Hyaluronan Receptors; Infusions, Intravenous; Maytansine; Mice; Patient Selection

To test whether BIWI 1 (bivatuzumab mertansine), an immunoconjugate of the humanized anti-CD44v6 monoclonal antibody BIWA 4 and the maytansinoid DM1, given simultaneously to fractionated irradiation improves local tumour control in vivo compared with irradiation alone.. For growth delay, FaDu tumours were treated with 5 intravenous injections (daily) of phosphate buffered saline (PBS, control), BIWA 4 (monoclonal antibody against CD44v6) or BIWI 1 (bivatuzumab mertansine) at two different dose levels (50 μg/kg DM1 and 100 μg/kg DM1). For local tumour control, FaDu tumours received fractionated irradiation (5f/5d) with simultaneous PBS, BIWA 4 or BIWI 1 (two dose levels).. BIWI 1 significantly improved local tumour control after irradiation with 5 fractions already in the lower concentration. The dose modifying factor of 1.9 is substantial compared to the majority of other modifiers of radiation response.. Because of the magnitude of the curative effect, this approach is highly promising and should be further evaluated using similar combinations with improved tumour-specificity.

Topics: Animals; Antibodies, Monoclonal, Humanized; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Survival; Combined Modality Therapy; Dose Fractionation, Radiation; Dose-Response Relationship, Radiation; Female; Flow Cytometry; Follow-Up Studies; Humans; Hypopharyngeal Neoplasms; Male; Maytansine; Mice; Tumor Burden

We have constructed a murine hybrid hybridoma that secretes a bispecific monoclonal antibody (mAb) by fusing a hybridoma secreting an anti-ansamitocins mAb with a hybridoma secreting an anti-human transferrin receptor (TfR) mAb that binds to human A431 epidermoid carcinoma cells. The bispecific mAb, reactive to both ansamitocins and TfR, was purified by a combination of hydrophobic column chromatography and hydroxyapatite high-performance liquid chromatography, and evaluated in in vivo experiments using human tumor cell-implanted nude mice. Ansamitocin P-3 targeted through one of the antigen combining sites of the bispecific mAb was potentially more effective in suppressing the growth of established A431 tumor xenografts implanted on nude mice than unconjugated ansamitocin P-3 or the immunoconjugate of ansamitocin P-3 and monospecific anti-ansamitocins antibody, and the targeted ansamitocin P-3 finally eradicated the tumor mass. The bispecific mAb also played an important role in reducing such undesirable side-effects of ansamitocin P-3 as the loss of body weight, the damage to liver functions and the decrease in the number of white blood cells.

Topics: Animals; Antibiotics, Antineoplastic; Antibodies, Monoclonal; Antibody Specificity; Carcinoma, Squamous Cell; Humans; Hybridomas; Immunotherapy; Immunotoxins; Maytansine; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Receptors, Transferrin; Transplantation, Heterologous

Twenty-nine patients with advanced or recurrent squamous cell carcinoma of the cervix who had failed standard therapy were treated with maytansine 1.2 mg/m2 intravenously once every 3 weeks. Only one partial remission was observed among the 29 patients (3%). There were no complete remissions. Stable disease was observed in 18 (62%) and progressive disease in 10 (35%). Adverse effects were infrequent and mild to moderate and consisted primarily of myelosuppression, weakness, and nausea and vomiting. This study shows that maytansine at the dose and schedule tested is essentially inactive in the treatment of advanced or recurrent squamous cell carcinoma of the cervix.

Topics: Adult; Aged; Carcinoma, Squamous Cell; Drug Evaluation; Female; Humans; Leukocyte Count; Leukopenia; Maytansine; Middle Aged; Neoplasm Recurrence, Local; Oxazines; Thrombocytopenia; Uterine Cervical Neoplasms

Topics: Adenocarcinoma; Antineoplastic Agents; Carcinoma, Squamous Cell; Cisplatin; Dianhydrogalactitol; Drug Evaluation; Etoposide; Female; Humans; Maytansine; Neoplasm Recurrence, Local; Pelvic Neoplasms; Piperazines; Razoxane; Research Design; Triazines