homoharringtonine and Melanoma

Four new and clinically relevant antineoplastic natural products are reviewed. Taxol is derived from the bark of the western yew. It promotes the formation of microtubule bundles which deform the cytoskeleton and interfere with mitosis. Although phase II efficacy testing is incomplete, taxol is effective in the treatment of patients with ovarian carcinoma and has some activity in patients with non-small cell lung cancer and melanoma. It remains untested against several other neoplasms. The chief toxicities of taxol are myelosuppression, mucositis, anaphylactoid reactions, and peripheral neuropathy. Homoharringtonine is the most active and abundant of the cephalotaxine esters derived from the genus Cephalotaxus. This agent appears to act at the ribosome to inhibit protein synthesis and has clinical activity in patients with acute myelogenous leukemia. The dose limiting toxicities of homoharringtonine are hypotension and myelosuppression. SKF 104864 and CPT-11 are derivatives of camptothecin which are still in early clinical trials. They are cytotoxic in vitro, acting through an interaction with topoisomerase I to induce DNA fragmentation. The spectra of activity and toxicity of SKF 104864 and CPT-11 are still undefined. All four of these new natural products offer possibilities for clinical activity for patients with a variety of malignancies.

Topics: Adenocarcinoma; Alkaloids; Antineoplastic Agents, Phytogenic; Camptothecin; Carcinoma, Squamous Cell; Chemical Phenomena; Chemistry; Drugs, Investigational; Harringtonines; Homoharringtonine; Humans; Infusions, Intravenous; Irinotecan; Melanoma; Paclitaxel; Phytotherapy; Plant Extracts; Plants, Medicinal; Topotecan

Cancer dose-finding trials aim at assessing the maximum tolerated dose (MTD) of a new treatment or combination. Owing to ethical constraint, they are based on adaptive designs, sequentially allocating patients to increased doses on the basis of previous responses. More recently, the concept of MTD has been extended to the largest concept of most successful or most desirable dose, based on efficacy criterion under toxicity restrictions. The aim of this paper is to present three main approaches proposed to estimate such a dose, in the setting of Phase I/II trials. Two case-studies allow to illustrate these new approaches.

Topics: Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Harringtonines; Homoharringtonine; Humans; Interferon alpha-2; Interferon-alpha; Leukemia, Myeloid, Acute; Maximum Tolerated Dose; Melanoma; Recombinant Proteins; Research Design

Topics: Alkaloids; Animals; Cell Line; Colony-Forming Units Assay; Harringtonines; Homoharringtonine; Humans; Leukemia L1210; Leukemia, Myeloid, Acute; Melanoma; Mice; Tumor Stem Cell Assay

Five phase II trials of the antitumor agent homoharringtonine were conducted in 80 patients who had advanced solid tumors. The five categories of solid tumors included malignant melanoma; sarcoma; and head and neck, breast, and colorectal carcinomas. The starting dose of homoharringtonine was 3.0-4.0 mg/m2 by short iv infusion daily X 5 days every 21 days. Seventy-eight of 80 patients had had prior chemotherapy and 49 had had prior radiation therapy. Among the 74 evaluable patients in the five tumor categories, there were no complete or partial remissions. Homoharringtonine was generally well-tolerated. Nausea and vomiting, diarrhea, and fever and chills were the most common side effects. Serious reversible cardiovascular toxicity, which occurred in three patients, included symptomatic hypotension in two and short runs of ventricular tachycardia in one. The investigations thus conclude that homoharringtonine given by intermittent schedule is an inactive drug against these solid tumors previously exposed to chemotherapy.

Topics: Adolescent; Adult; Aged; Alkaloids; Bone Marrow; Breast Neoplasms; Carcinoma; Colonic Neoplasms; Drug Evaluation; Female; Harringtonines; Head and Neck Neoplasms; Heart; Homoharringtonine; Humans; Hypotension; Male; Melanoma; Middle Aged; Rectal Neoplasms; Sarcoma

Antitumor activities of harringtonine(HA) and homoharringtonine(HO) both belong to cephalotaxus alkaloids were compared with those of vinca alkaloids, vincristine (VCR) and vinblastine (VLB). HA and HO had significant activities against P388 leukemia, L1210 leukemia and B16 melanoma by intraperitoneal injection comparable to VCR and VLB. The therapeutic index (LD10/ED50) of HA and HO in B16 melanoma system was 1.90 and 2.31, while those of VCR and VLB were 1.38 and less than 1.00, respectively. The oral administration of these cephalotaxus alkaloids evoked a significant antitumor activity but that of vinca alkaloids induced no activity against P388 and B16 melanoma. The efficacy of HO on various tumor systems was equal or greater than that of HA when comparison was made between these two cephalotaxus alkaloids. In contrast to VCR and VLB, HA and HO demonstrated moderate activity against P388/VCR, a subline of P388 resistant to vincristine. The intraperitoneal injection of VCR or VLB produced an increase in the mitotic index of P388 cells as compared with the control values, but HA or HO decreased it. HA and HO, cephalotaxus alkaloids are a new class of active compounds of plant origin which may differ from the vinca alkaloids in the mechanism of antitumor activity.

Topics: Administration, Oral; Alkaloids; Animals; Antineoplastic Agents, Phytogenic; Harringtonines; Homoharringtonine; Injections, Intraperitoneal; Leukemia P388; Male; Melanoma; Mice; Mitotic Index; Neoplasms, Experimental; Vinblastine; Vincristine