Von Hoff Dd

Taxol: a new and effective anti-cancer drug.

Taxol is a new anti-cancer drug that is a natural product derived from the bark of the Pacific Yew tree. The drug promotes polymerization and stabilization of tubulin to microtubules and interferes with the mitotic spindle. Clinical trials indicate that taxol is effective in the treatment of patients with refractory ovarian cancer, breast cancer, malignant melanoma and probably other solid tumors. Toxicities include anaphylactoid reactions, leukopenia, peripheral neuropathy and oropharyngeal mucositis. Increased supplies of the drug are required to support further phase II and III testing.

Effects of Taxotere and taxol on in vitro colony formation of freshly explanted human tumor cells.

Taxotere (RP 56976, NSC 628503) is a new semisynthetic analog of taxol (NSC 125973) with promising antitumor activity in a variety of preclinical screening systems. Clinical responses after treatment with taxol have been observed in ovarian cancer, breast, lung cancer and melanoma. Both agents act through induction of microtubule polymerization. We have studied and compared the antiproliferative action of Taxotere and taxol against a variety of freshly explanted human tumor specimens using an In vitro soft agar cloning system. Final concentrations of 0.025–10 μg/ml were used for both agents in short-term (1 h) or continuous (14 days) incubations. Taxotere was studied using a 1 h incubation in a total of 167 tumor specimens of which 85 (51%) were evaluable. At 10μg/ml, Taxotere inhibited 32 out of 78 (41%) specimens (colony formation ≤0.5 ± control). Cytotoxicity of Taxotere was observed against breast, lung, ovarian, colorectal cancer and melanoma tumor colony forming units. For comparison, 227 specimens were exposed to taxol for 1 h. At 10μg/ml, 32 out of 97 evaluable specimens (33%) were significantly inhibited. Cytotoxicity was observed against breast, lung, ovarian, colorectal cancer and melanoma tumor colony forming units. In head-to-head comparisons, 29 specimens were found more sensitive to Taxotere than taxol, while only 13 were more sensitive to taxol than to Taxotere. These data indicate that cross-resistance between the two agents is incomplete and that on a concentration basis Taxotere is more cytotoxic than taxol in the majority of human primary tumor specimens evaluated.

A phase I clinical and pharmacokinetic study of the topoisomerase I inhibitor topotecan (SK&F 104864) given as an intravenous bolus every 21 days.

Topotecan (SK&F 104864) is a novel antitumor agent whose mechanism of action is inhibition of the DNA unwinding protein topoisomerase I. An analog of camptothecin, topotecan was designed to be more water soluble in an effort to decrease the severe and sporadic toxicities experienced during phase I/II trials of the parent compound. In this phase I clinical and pharmacological trial, topotecan was given as a bolus intravenous (i.v.) infusion over 30 min every 21 days. A total of 42 patients entered the study, receiving doses ranging from 2.5 to 22.5 mg/m2. The maximum tolerated dose (MTD) of topotecan given in this schedule was 22.5 mg/m2. Myelo-suppression, primarily neutropenia, was dose-limiting. The extent of prior therapy did not predict for more severe neutropenia. Non-hematologic toxicities were mild and included low-grade to moderate fever, nausea, vomiting, alopecia, diarrhea and skin rashes. There were no objective partial or complete responses, although there was a suggestion of antitumor activity in three patients. Topotecan undergoes pH-dependent hydrolysis of the lactone ring; only the closed, lactone form is active. The lactone form predominated during infusion, with hydrolysis occurring rapidly following the end of infusion. There were linear relationships between dose administered and peak plasma lactone concentrations as well as AUC lactone to AUC total. The lactone was rapidly cleared from plasma with a total body clearance of 25.7 (±6.7) l/h/m2. The plasma lactone concentration declined rapidly with a harmonic mean terminal half-life of 3.4 (±1.1) h. Lactone hydrolysis and renal excretion were the major routes of elimination. Topotecan given as an i.v. bolus every 21 days proved to be a well-tolerated drug with primarily hematological toxicity.

Activity of CPT-11 (irinotecan hydrochloride), a topoisomerase I inhibitor, against human tumor colony-forming units

CPT-11 (irinotecan hydrochloride, 7-ethyl-10-[4-(piperidino)-1-piperidino] carbonyloxy-camptothecin) is a semisynthetic camptothecin derivative developed in Japan. The inhibitory activity of CPT-11 against human tumor colony-forming units from freshly explanted human tumors was explored using a soft agar cloning system. Final CPT-11 concentrations of 0.3-3.0 micrograms/ml were used for a 1 h exposure. At a concentration of 3.0 micrograms/ml antitumor activity was seen against colorectal, ovarian, nonsmall-cell lung, breast cancer and mesothelioma colony-forming units. CPT-11 should have activity against a broad spectrum of tumors in patients.

The impact of phase I clinical trials on the quality of life of patients with cancer.

This prospective, non-randomized study was designed to evaluate the quality of life (QOL) of cancer patients receiving new cytoxic therapy. QOL was measured using a linear analog self assessment scale (LASA). Cancer patients who received a phase I agent (n = 45) had no significant changes in any of the Individual QOL variables, overall QOL (p = 0.77) or performance status (p = 0.08) following one course of phase I therapy. However, patients who were not eligible for entry on a phase I protocol and who received supportive care (n = 10) experienced significant decreases in overall QOL (p = 0.02) and performance status (p = 0.003) after 1 month of follow-up. This pilot study suggests that participation in phase I trials does not adversely affect ones QOL.

Neuropeptide receptor status in human tumor cell lines.

Tumor types expressing a neuroendocrine phenotype secrete neuropeptides with paracrine or autocrine growth factor activity. The efficacy of these paracrine or autocrine loops depends on the expression of specific receptors on tumor cells. Once specific receptors are identified, specific neuropeptide antagonists disrupting paracrine and autocrine loops could be potential treatments in neuropeptide-secreting tumors. In the present study, 11 human tumor cell lines representing astrocytoma, lymphoma, and pancreatic, prostate, lung and colon carcinomas were examined for expression of five different neuropeptide receptors (cholecystokinin, neurotensin, vasopressin, tachykinine substance P and cannabinoid) using RT-PCR and radioligand binding. The presence of various neuropeptide receptors in different human cancer cell lines supports development of new antitumor treatments based on disruption of neuropeptide autocrine growth pathways.

Activity of TER286 against human tumor colony-forming units.

Glutathione S-transferase (GST) isozymes have been shown to be elevated in many human cancer types as compared to normal tissues. TER286, one in a class of glutathione-based GST-activated cytotoxins, was tested in a soft agar cloning assay to determine its in vitro activity against primary human tumor colony-forming units. Breast and lung specimens from patients who had received prior therapy and those who were previously untreated were exposed to TER286 at concentrations of 1, 10 and 50 microM using both 1 h and continuous exposures. Overall in vitro responses (50% or less survival compared to untreated controls) were observed in 0% (0/14), 14% (2/14) and 29% (4/14), respectively, in specimens exposed to TER286 for 1 h, and in 5% (2/41), 10% (4/41) and 61% (25/41), respectively, in specimens exposed to TER286 continuously. TER286 has cytotoxic activity against both breast and lung cancer colony-forming units, and demonstrates a concentration-response effect. At 50 microM, there is a significant difference between 1 h and continuous exposures in head-to-head comparisons. These data suggest that TER286 can be activated in human tumor colony-forming units and should be pursued as a treatment candidate for patients whose tumors are resistant to drug treatment based on up-regulation of GST.

Phase I study with the DNA sequence-specific agent adozelesin.

Adozelesin, a synthetic analog of the antitumor antibiotic CC-1065, is a novel cytotoxic agent which inhibits DNA synthesis by binding to the minor groove of the DNA helix. Preclinical studies have shown a broad spectrum of activity against a variety of murine and human tumor xenograft models. We conducted a phase I study of adozelesin to (i) determine a recommended dose for phase II testing using a 10 min i.v. infusion, (ii) characterize the toxic effects of the drug using this schedule and (iii) document any antitumor activity observed. Adozelesin was administered as an i.v. infusion every 6 weeks. CBC and biological parameters were performed weekly. The starting dose of 10/jg/m2, corresponding to 1/30 the mouse equivalent lethal dose, was escalated, according to a modified Fibonacci scheme, until dose-limiting toxicity was encountered. Forty-seven adult patients with solid malignancies were entered in the study. Successive dose levels used were 10, 20, 33, 50, 70, 105, 120, 150 and 180/tg/m2. The main toxic effect was myelosuppression, which was dose limiting. The maximally tolerated dose was defined as 180//g/m2. A minor response with a 4 month duration was reported in one previously treated patient with melanoma. We conclude that the recommended phase II dose of adozelesin given as a 10 min infusion is 150//g/m2, repeated every 4 weeks.

Phase II study of 13-cis-retinoic acid and interferon-alpha 2a in patients with advanced squamous cell lung cancer.

The combination of interferon (IFN)-alpha 2a and 13-cis-retinoic acid (13-cRA) has demonstrated significant antitumor activity in patients with advanced squamous cell cancer of the skin and cervix. We performed a prospective phase II trial of this combination in patients with locally advanced or metastatic squamous cell lung cancer. Twenty-one patients were enrolled on the study. All patients were evaluable for toxicity and 17 were evaluable for response, four with locally advanced and 13 with metastatic disease. One partial response was obtained in a patient with locally advanced disease. Toxicity consisted mainly of constitutional side effects (fatigue, anorexia), which resulted in eight patients coming off-study. The combination of IFN-alpha 2a and 13-cRA is unlikely to exhibit significant clinical activity in patients with metastatic squamous cell lung cancer, but activity in patients with locally advanced disease has not been excluded.

COMPARISON OF DX-8951F AND TOPOTECAN EFFECTS ON TUMOR COLONY FORMATION FROM FRESHLY EXPLANTED ADULT AND PEDIATRIC HUMAN TUMOR CELLS

DX-8951f, which shows great therapeutic potential, was tested in the human tumor cloning system in adult and pediatric tumor types against which topotecan has been active. In 47 tumors from adults, DX-8951f had definite cytotoxic activity in a concentration-dependent manner with both 1 h and continuous exposures. Topotecan was minimally effective using a 1 h exposure and showed concentration-dependent inhibition with continuous exposure. In head-to-head comparisons at 1 h exposure against adult tumors, DX-8951f was significantly more effective at 0.1 and 1.0 microg/ml than topotecan. In head-to-head comparisons (continuous exposure), 1.0 microg/ml DX-8951f was more effective than topotecan at 1.0 microg/ml in adult tumors, including three of four head and neck, one of two kidney, two of five liver, six of 10 non-small cell lung, five of eight ovarian, four of eight prostate tumors, and in single specimens of breast, mesothelioma, colon and small cell lung tumors. With continuous exposure, DX-8951f and topotecan were equally effective at equimolar concentrations. The maximum tolerated dose for DX-8951f is 3 times that of topotecan, so higher doses of DX-8951f could be administered to patients. DX-8951f is a promising new antineoplastic agent with significant activity against tumors taken directly from patients.